Next Article in Journal
Exosomes and Hepatocellular Carcinoma: From Bench to Bedside
Next Article in Special Issue
PD-L1 Expression in Systemic Immune Cell Populations as a Potential Predictive Biomarker of Responses to PD-L1/PD-1 Blockade Therapy in Lung Cancer
Previous Article in Journal
The First Report of Polymorphisms and Genetic Features of the prion-like Protein Gene (PRND) in a Prion Disease-Resistant Animal, Dog
Previous Article in Special Issue
Role of PD-L1 Expression in Non-Small Cell Lung Cancer and Their Prognostic Significance according to Clinicopathological Factors and Diagnostic Markers
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 20
Issue 6
10.3390/ijms20061405
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

PD-1 Ligand Expression in Epithelial Thyroid Cancers: Potential Clinical Implications

by
Salvatore Ulisse
1,
Chiara Tuccilli
1,
Salvatore Sorrenti
1,
Alessandro Antonelli
2,
Poupak Fallahi
2,
Eleonora D’Armiento
3,
Antonio Catania
1,
Francesco Tartaglia
1,
Maria Ida Amabile
1,
Laura Giacomelli
1,
Alessio Metere
1,
Nicola Cornacchini
4,
Daniele Pironi
1,
Giovanni Carbotta
1,
Massimo Vergine
1,
Massimo Monti
1 and
Enke Baldini
1,*
1
Department of Surgical Sciences, “Sapienza” University of Rome, 00161 Rome, Italy
2
Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
3
Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, 00161 Rome, Italy
4
Department of Surgery, S. Kliment Ohridski University, 1504 Sofia, Bulgaria
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(6), 1405; https://doi.org/10.3390/ijms20061405
Submission received: 25 February 2019 / Revised: 14 March 2019 / Accepted: 17 March 2019 / Published: 20 March 2019
(This article belongs to the Special Issue PD-L1, A Master Regulator of Immunity)
Browse Figure
Versions Notes

Abstract

:
The new immunotherapy targeting the programmed cell death 1 (PD-1) receptor and its cognate ligand PD-L1 has renewed hopes of eradicating the most difficult human cancers to treat. Among these, there are the poorly differentiated and anaplastic thyroid cancers, unresponsive to all the therapies currently in use. In the present review we will summarize information regarding the expression of PD-L1 in the different thyroid cancer histotypes, its correlation with clinicopathological features, and its potential prognostic value. Then, we will evaluate the available data indicating the PD-1/PD-L1 axis as a promising target for thyroid cancer therapy.

1. Thyroid Cancer: An Overview

Thyroid cancer represents the most common endocrine malignancy and the fifth most common cancer in women in the United States [1]. Its annual incidence has tripled over the last twenty years, with an average annual rate of 21.4% in female, and of 7.3% in male in the years 2011–2015 [1,2,3]. Most thyroid neoplasms are well-differentiated thyroid cancers (WDTC) derived from epithelial follicular cells, comprising the papillary thyroid carcinoma (PTC) and the follicular thyroid carcinoma (FTC) histotypes, which may progress towards the poorly differentiated thyroid carcinoma (PDTC) and the anaplastic thyroid carcinoma (ATC) [4]. Although originating from the same cell type, thyroid cancers display different morphological features, functional behavior, and grade of differentiation as a result of heterogeneous genetic alterations [4,5,6,7]. Among these, the most frequent are activating point mutations of the BRAF and RAS oncogenes, and chromosomal translocations of the RET (REarranged during Transformation) and NTRK1 (Neurotrophic Tyrosine Kinase Receptor 1) genes, which lead to the activation of a common carcinogenic pathway, i.e., the MAPK/ERK signaling [8,9].
Thyroid nodules are very common, affecting 19% to 67% of the adult population, but only about 5% of them harbor a malignant lesion [10]. To date, fine-needle aspiration cytology (FNAC) represents the main diagnostic tool for the evaluation of both palpable and non-palpable thyroid nodules [10,11,12]. However, in the case of indeterminate atypia or follicular proliferation, FNAC fails to discriminate adenomas from FTC or follicular variants of PTC (FVPTC), which implies the overtreatment of many patients subjected to unnecessary thyroid resection. Different molecular diagnostic approaches have been attempted to overcome this inherent limitation of FNAC and to refine preoperative diagnosis [11,12]. In recent years, the improvement of knowledge concerning the molecular changes underlying thyrocyte malignant transformation, along with remarkable progresses of high-throughput genotyping techniques, has allowed the introduction of different molecular diagnostic tests with increasingly satisfying performances, e.g., ThyroSeq, Afirma, Rosetta GX Reveal [12]. Molecular markers have also been evaluated for prognostic purposes, in order to ameliorate the stratification of patients in follow-up. Actually, the prognosis of thyroid cancer is largely favorable, with 5-year-survival rates of close to 100% for low-stage (I and II) WDTC, 90% for stage III PTC, 70% for stage III FTC, and 50% for stage IV [1,2,3,10]. However, the current TNM staging systems make a coarse prediction of recurrence or mortality risk, including patients in the same stage with considerably different disease-free survival and overall survival [13,14,15]. To this end, the European (ETA) and the American Thyroid Associations (ATA) proposed new guidelines to estimate the risk of recurrences in which TNM parameters are combined with additional clinical features such as histological variants, multifocality, outcome of post-ablative whole-body scan, vascular invasion, extrathyroidal extension, and serum thyroglobulin levels [15,16]. Despite this, patients within the same risk group still show diverse behavior in terms of disease-free interval. Recently introduced mutational markers offer high sensitivity and specificity in identifying high-risk thyroid cancers. Interestingly, the same multigene panels used to detect tumor-associated genetic alterations in thyroid FNA, like ThyroSeq, are also able to categorize a small subset of thyroid cancers with the most unfavorable outcomes, providing cancer risk stratification even before surgery [12]. This novel approach is promising, although it needs extensive validation on large case studies and integration with clinical parameters of prognostic relevance.
Lastly, an important issue still to be solved is the treatment of patients affected by advanced or undifferentiated thyroid cancers, which are more prone to disease recurrences and cancer-related deaths because refractory to adjuvant therapy with 131I [1,2,3,10,17,18,19]. In these patients, external beam radiation and chemotherapy do not elicit effective therapeutic responses, and thus new therapeutic strategies aimed at eradicating aggressive thyroid tumors are urgently needed [7,17,20,21,22,23].

2. Dysregulation of the Immune System in Thyroid Cancer

According to the Cancer Immunoediting Hypothesis, tumor infiltration by cells of the innate and adaptive immune systems reflects a physiological process aimed at eliminating malignant cells, in early as well as in advanced tumors and in metastases [24]. The ability of cancer cells to avoid the immune damage by disabling components of the host immune system is now considered a hallmark of cancer [25]. In particular, it has been shown that the immune response is turned off by a variety of mechanisms, including: i) inactivation of cytotoxic T lymphocytes (CTL) and natural killer (NK) cells by secreting immunosuppressive factors (i.e., TGF-β, indoleamine 2,3-dioxygenase, IL-10 and VEGF); ii) recruitment of immunosuppressive cells such as myeloid-derived suppressor cells and regulatory T cells (Treg); iii) expression of inhibitory ligands for the immune checkpoint receptors CTLA-4 (cytotoxic T lymphocyte antigen 4) and PD-1 (programmed cell death 1), present on the surface of activated T lymphocytes [26,27,28,29,30,31,32].
WDTCs are supposed to be poorly immunogenic because of their low mutational burden due to low neoantigen expression [33]. However, they are infiltrated by several host immune cells, including NK, tumor-associated macrophages, mast cells, dendritic cells, B and T lymphocytes [34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51]. Malignant thyrocytes are able to counteract these immune cells in different ways, for example, by inducing T-lymphocyte anergy, recruiting Treg, stimulating formation of tolerogenic antigen presenting cells (APC), downregulating neoantigen recognition, and expressing immune checkpoint molecules. The intratumoral density of immune cells, along with the expression of immunosuppressive markers, have been correlated with the thyroid differentiation score (TDS) of tumors and the BRAF status. Namely, low TDS and BRAFV600E mutation were found to entail enrichment of dendritic cells, Treg, macrophages, and mast cells in PTC, together with higher expression levels of CTLA-4 and PD-L1 [36,52]. The immuno-suppressive environment of thyroid cancers is sustained also by indoleamine 2,3-dioxygenase production by tumor cells, associated with an increased Treg infiltrate and more aggressive clinicopathological features, such as extra-thyroidal extension or multifocality [33]. In essence, the ensemble of molecular mechanisms that modulate host immune cells within thyroid tumor microenvironment has immune escape as the final result, whose degree was shown to correlate with more aggressive tumor behavior [34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51].
In the present review, we’ll focus on the available data regarding the expression of PD-L1 and PD-L2 in thyroid cancer tissues and its possible clinical implications in terms of prognosis and therapy for the most aggressive thyroid cancers.

3. Programmed Cell Death 1 (PD-1) and Its Ligands

The PD-1, also known as cluster of differentiation 279 (CD279), is a type I transmembrane protein member of 288 amino acids encoded by the PDCD1 gene localized on chromosome 2q37.3 (NCBI Gene ID: 5133) [53,54]. The PD-1 is a member of the B7-CD28 immunoglobulin superfamily, and it is expressed by T and B lymphocytes and by NK cells following activation [55]. Specifically, T cell activation is based on the interaction of the T cell receptor (TCR) with MHC molecules presenting the antigen, and is tightly regulated by different costimulatory molecules which can either potentiate or inhibit T cell response, including the CD28, the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and the PD-1 (Figure 1) [55].
Both CTLA-4 and PD-1 exert an inhibitory action on T cells, which is thought to prevent autoimmunity and to reduce collateral tissue damage by restraining the immune reaction in chronic infections, but it is also implicated in tumor-induced immunosuppression [55]. CTLA-4 shares the same ligands of CD28, namely the B7-1 (CD80) and the B7-2 (CD86). However, upon binding to these molecules, CD28 triggers a strong costimulatory signal for T cell activation, while CTLA-4 behaves as a potent inhibitor. Two different type I transmembrane proteins, structurally related to the B7 family, bind to the PD-1 receptor, namely the PD-L1 (B7-H1 or CD274) and the PD-L2 (B7-DC or CD273) [54,55]. The PD-L1 (CD274) gene is located at the chromosome 9p24.2 and encodes a 290 aa protein of 33.3 kDa (NCBI Gene ID: 29126), while the PD-L2 (PDCD1LG2) gene is located at the chromosome 9p24.1 and encodes a 273 aa protein of about 31 kDa (NCBI Gene ID: 80380). PD-L1 and PD-L2 have been described in various healthy cells and organs, e.g., lung, heart, bladder, vascular endothelium, spleen, mesenchymal stem cells, pancreatic islets, astrocytes, neurons, and keratinocytes, although with distinct expression patterns. PD-L1 has also been detected in immune-privileged sites like the eye and the placenta, where it increases from the fourth month of gestation [56]. Among hematopoietic cells, PD-L1 is constitutively expressed on T and B lymphocytes, dendritic cells, macrophages, mesenchymal stem cells and bone marrow-derived mast cells [57]. In contrast, PD-L2 expression is restricted to activated dendritic cells, macrophages, bone marrow-derived mast cells, and the majority of peritoneal B1 cells [57]. During infection or inflammation, PD-1 and its ligands are engaged in regulating the extent of immune responses through inhibition of TCR-mediated lymphocyte proliferation, blockade of cytokine secretion, and induction of naive T cell to differentiate in Treg. Furthermore, the PD-1/PD-L pathway plays a key role in the maintenance of peripheral tolerance, hampering detrimental actions of self-reactive T cells escaped negative selection in the thymus [56]. Actually, abnormal activation of the PD-1/PD-L interaction appear to be of major clinical relevance in several autoimmune diseases, such as diabetes mellitus type I, systemic lupus erythematosus, autoimmune encephalomyelitis, inflammatory bowel disease, rheumatoid arthritis, myasthenia gravis, and autoimmune hepatitis [56]. PD-1/PD-L pathway is also considered a fundamental player of host immune escape that induces suppression of TCR-mediated activation and inhibits T cell cytolysis. Additionally, emerging evidence suggests an anti-apoptotic role of cytoplasmic PD-L1, which may confer a growth advantage to cancer cells independently from its immune suppression role. This property of PD-L1 was discovered starting from the observation that resveratrol, a polyphenol compound endowed with anticancer effects, can induce p53-dependent apoptosis in malignant cells by a mechanism that is jammed by PD-L1 upregulation. In particular, resveratrol causes nuclear accumulation of cyclooxygenase-2 (COX-2), as well as activation and nuclear translocation of mitogen-activated protein kinases (ERK1/2). COX-2 complexes with ERK1/2 and p53, and binds to promoters of certain p53-responsive genes initiating apoptosis [58]. Cytoplasmic accumulation of PD-L1 leads to retention of COX-2 in the cytoplasm, thus preventing its pro-apoptotic action [59].

4. Expression and Clinical Utility of PD-1 Ligands in Thyroid Cancer

Over the last few years, the expression of PD-L1 and PD-L2, mainly PD-L1, in different thyroid cancer histotypes has been investigated by several studies [37,41,42,43,44,45,46,60,61,62,63,64,65,66,67,68]. As reported in Table 1, PD-L1 protein has been assessed by means of immunohistochemistry (IHC) [37,42,43,44,45,46,62,65,66,67,68], while few studies evaluated PD-L1 at the mRNA level (Table 2) [41,42,63,64]. The results obtained indicate that routine measurement of PD-L1 expression in thyroid cancer specimens could turn useful for both patient’s diagnosis and prognosis, as well as for the identification of patients that could benefit from anti-PD-1/PD-L1 therapies.

4.1. PD-L1 Expression and Thyroid Cancer Diagnosis

The majority of studies examining PD-1 ligands in thyroid cancer have been aimed at evaluation of their prognostic relevance by correlating the expression levels with patients’ clinicopathological features, while some studies have attempted to estimate the diagnostic value of PD-1 ligands in thyroid cancer [42,69,70,71]. Cunha and colleagues, by means of IHC analysis of 293 DTC, 114 benign thyroid lesions and 5 normal tissues, found that PD-L1 protein did not have a diagnostic utility [42]. However, more recently, it has been reported that PD-L1 expression may help to distinguish aggressive forms of encapsulated FVPTC (EFVPTC) from the noninvasive ones, reclassified as non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) at low risk of malignancy [69,70,71,72]. In particular, Fu and colleagues retrospectively analyzed the expression of PD-L1, by means of IHC, in 52 NIFTP and 45 invasive EFVPTC in comparison with 40 benign nodules [66,67]. The authors found no significant differences in PD-L1 cytoplasmic staining between NIFTP and thyroid benign lesions, while a considerable increase was observed between NIFTP or benign lesion and invasive FVPTC [69,70,71]. Since the majority of NITPF are diagnosed as indeterminate lesions in clinical practice [73,74], the opportunity to discriminate NIFTP from invasive EFVPTC based on PD-L1 assessment should improve the diagnostic accuracy and the clinical management of these patients, reducing the number of those undergoing surgical overtreatment.

4.2. PD-1 Ligand Expression and Thyroid Cancer Prognosis

As mentioned above, the majority of studies evaluating the expression of PD-L1 in thyroid cancer have been performed by IHC, using different tissue preparations, processing procedures, detection antibodies (clone E1L3N, ab82059, Ab174838, MABC290, 22C3 and SP142), cut-off values, and control tissues when available (i.e., benign lesions or normal matched tissues) [37,42,43,44,45,46,62,65,66,67,68]. Also, interpretations of IHC results (i.e., membranous staining and/or cytoplasmic staining of tumor cells) diverge in the different reports. In this context, it may be worth considering that in clinical trials with anti-PD-1/PD-L1 directed therapies, membranous but not cytoplasmic staining was considered in patient selection [44,75,76,77]. In fact, only the PD-L1 present on the membrane of tumor cells is theoretically active in inhibiting PD-1 positive immune cells. As a consequence, cytoplasmic staining should be considered as a negative result in PD-L1 immunodetection. On the whole, from the various studies recapitulated in Table 1 and Table 2, it emerges the absence of correlation between PD-L1 levels and clinicopathological parameters, while data regarding PD-L1 and disease-free survival (DFS)/disease-free interval (DFI) are discordant.
By analyzing clinical and biochemical data of a study comprising 507 PTC patients, available on the cBioPortal, we found a statistically significant correlation between higher levels of PD-L1 mRNA and lymph node metastasis, extrathyroidal invasion and DFS (Table 2) [8,63]. Analogously, a significant association between PD-L1 protein and DFS was observed in two large case studies (Table 1) [43,45]. It is also worth mentioning that in 4 out of 8 reports, a positive association between PD-L1 expression and the presence of BRAFV600E mutation, known to induce a more aggressive tumor behavior, was noticed [8,9,37,64,67]. In agreement, Brauner and colleagues showed that thyroid cancer cell lines with BRAFV600E mutation have higher baseline levels of PD-L1 mRNA compared to those harboring the BRAF wild type [78]. These findings appear to corroborate the reported ability of BRAFV600E signaling to modulate the immune response [37]. In fact, besides inducing PD-L1 expression, BRAFV600E has been shown in thyroid cancers to increase suppressive immune cell infiltration (Treg) [37]. A recent meta-analysis by Aghajani and colleagues described a moderate quality evidence from 4 studies, including 721 patients, which testified a significant association between PD-L1 positivity and poor survival in thyroid cancer patients, with a hazard ratio (HR) of 3.73 (C.I. 2.75–5.06) [79]. From the same meta-analysis, a significant association also emerged between increased PD-L1 and tumor recurrence [76]. These variations of PD-L1 levels do not seem to be due to increases in gene copy number, as indicated by a genetic screening of ATC and advanced DTC that documented co-amplification of PD-L1 and PD-L2 genes in 5 out of 196 ATC, and in none of 583 DTC analyzed [80]. Altogether, these findings point toward the PD-L1 as a possible prognostic marker useful to identify thyroid cancer patients with aggressive disease.
Regarding PD-L2 expression in thyroid tumors, to the best of our knowledge, only two studies have been performed so far [64]. One reported that PD-L2 mRNA levels increased in 35.1% and decreased 25.5% of PTC, but decreased in the majority of ATC, compared to control tissues [64]. In addition, higher expression of PD-L2 was found to be associated with the presence of the BRAFV600E and lymph node metastasis, but not with other clinicopathological features or DFI [64]. The same study evidenced a positive correlation between PD-L1 and PD-L2 expression. In the second one, Bastman and colleagues analyzed the expression of PD-L2 mRNA in a case study consisting of 92 DTC, and found no association between PD-L2 mRNA level and tumor size or lymph node metastasis [41]. In any case, further investigations on larger case studies and examination of protein levels are required to clarify the role of PD-L2 in thyroid cancer progression and its clinical utility.

4.3. Anti-PD-1/PD-L1 Directed Therapies and Thyroid Cancer

Over the last decade, the considerable increase of our knowledge about mechanisms underlying the ability of cancer cells to elude the detrimental action of the immune system has led to a renewed interest for immune-based therapy in oncology, especially for hard-to-treat cancers, including the poorly differentiated and frankly anaplastic thyroid cancers [74,81]. In particular, the recognition that cancer cells express on their plasma membrane immune checkpoint molecules, such as PD-1 and CTLA-4 ligands, has headed to the generation of monoclonal antibodies capable of preventing tumor-induced exhaustion of infiltrating lymphocytes. Several antibodies targeting the PD-1/PD-L1 pathway, reported in Table 3, have been approved by the Food and Drug Administration for the treatment of multiple cancer types, including melanoma, non-small cell lung cancer, Hodgkin’s lymphoma, renal cell carcinoma, gastric and urothelial bladder cancers, and Merkell cell carcinoma [82,83].
The objective response rate to PD-1/PD-L1 directed therapies varies from 13 to 43% in different tumor types [83]. The best responses are generally observed in patients with high tumor expression of PD-L1 and high numbers of tumor-infiltrating immune cells, particularly CD8+ T cells [83,84,85,86]. In this context, the recent observations by Kim and colleagues are of particular interest, whereby, by means of an immune gene signature comprising the PD-L1 and CTLA-4 genes, the canonical BRAF-like and RAS-like PTC were classified into 2 subgroups each: BRAF-IR (immunoreactive) and RAS-IR, characterized by up-regulation of immune-related genes and tumor infiltration by several immune cell subtypes, including T cells; and BRAF-ID (immunodeficient) and RAS-ID, characterized by low expression of immune-related genes and low infiltration of immune cells [63,87]. Confirming the studies mentioned above, the authors showed that BRAF-IR PTC had higher expression of CTLA-4 and PD-L1, which renders this PTC subgroup a potential candidate for immune checkpoint therapies [87].
At present, no information from clinical trials with anti-PD-1/PD-L1 directed therapies enrolling patients affected by aggressive thyroid cancers is available. However, different preclinical studies demonstrated the efficacy of PD-1/PD-L1 axis blockade in restraining growth of ATC-derived cell lines injected in mice [78,88,89]. In particular, it has been shown that simultaneous administration of an anti PD-L1 antibody (10F.9G2) and a BRAF inhibitor (PLX4720) or lenvatinib (multitargeted tyrosine kinase inhibitor of VEGFR1-VEGFR3, FGFR1-FGFR4, PDGFRα and RET) synergistically reduced tumor volume in an immunocompetent murine model bearing implanted syngeneic ATC [78,88]. In these experiments, it was also found that treatment with anti-PD-L1 antibody resulted in an increased tumor infiltration of CD8+ T cell with augmented cytotoxic profile [78,88]. Kollipara and colleagues reported the encouraging case of a 62-year-old male who, following ATC diagnosis, was initially treated by thyroidectomy with lymph node dissection [90]. Subsequently, the positron emission tomography (PET) revealed the presence of a mass in the thyroid bed, and metastases in the supraclavicular region as well as in the upper lobes of right and left lungs. The patient was then treated with doxorubicin and cisplatin, to which he was unresponsive, as judged by the progression of lung metastases, and a second-line paclitaxel treatment was equally ineffective. Following the identification of the BRAFV600E mutation and PD-L1 protein by IHC in tumor tissue, the patient was treated with vemurafenib (BRAF inhibitor) and nivolumab. Whereupon, the patient experienced a continued reduction of the metastatic lesions with complete radiographic and clinical remission of the disease 20 months after the beginning of nivolumab therapy [90]. In another study, performed at the MD Anderson Cancer Center, 12 ATC patients in treatment with different kinase inhibitors (5 of which were treated with lenvatinib, 6 with dabrafenib plus trametinib, and 1 with trametinib alone) started to receive pembrolizumab in combination with kinase inhibitors at the time of disease progression [91]. Of these patients, 5 (42%) had a partial response, 4 (33%) exhibited stable disease, and 3 (25%) had progressive disease [91]. Very recently, the results of a phase 1B clinical trial (NCT02054806) evaluating the efficacy of pembrolizumab monotherapy in patients with PD-L1-positive advanced DTC have been reported [92]. Twenty-two patients were enrolled in the study and treated with pembrolizumab at the dose of 10 mg/Kg administered every two weeks up to 24 months. Eighteen patients (82%) had low-grade treatment-related adverse effects, including diarrhea (32%), fatigue (18%) and rash (14%), but no patient was discontinued due to deleterious side effects [92]. A partial response to treatment was observed in 2 patients (overall response rate of 9%), 13 patients experienced a stable disease (59%), while 7 had a progressive disease [92]. At the moment, there is much interest in the results of an ongoing phase II clinical trial evaluating pembrolizumab on metastatic or locally advanced ATC patients, that should be completed by October 2019 (NCT02688608) [93]. This is a multi-center, open-label trial estimated to enroll at least 20 ATC patients, aimed at assessing the therapeutic effects of pembrolizumab administered at 200 mg intravenously every 3 weeks for up to 18 months.
Since the activation of the MAPK signaling in thyroid cancer has been shown to negatively modulate the immune response in the tumor microenvironment, it is likely that targeted therapies directed against this pathway may revert the immune suppression due to abnormal kinase activation [94]. For example, Sorafenib, a multitargeted antiangiogenic tyrosine kinase inhibitor, was shown to reduce Treg numbers and to inhibit their function in an orthotopic mouse model of hepatocellular carcinoma [95]. Thus, a strategy that could be worth exploring in approaching thyroid cancer is the combination of immune and targeted therapies [90,94]. In this regard, a phase 1b/2 clinical trial (NCT02501096) employing pembrolizumab plus lenvatinib is currently underway with patients affected by selected solid tumors, including thyroid cancers. The study is estimated to be completed by February 2020 [88,94,95,96,97].

5. Conclusions

The information so far available suggests that PD-L1 could represent a useful prognostic marker for risk stratification of thyroid cancer patients, and that anti-PD-1/PD-L1 directed therapies could be a valid option for patients affected by the most aggressive thyroid cancers, such as PDTC and ATC, unresponsive to the currently available therapies. Some issues, however, still remain to be addressed. In particular, the standardization of the IHC techniques, the interpretation of PD-L1 immunoreactivity in cancer tissues, and a more reliable characterization of biomarkers capable of predicting patients’ response to anti PD-1/PD-L1 therapies.

Author Contributions

All authors have significantly contributed to the first draft of the manuscript, to its revisions, and they all approved its final form.

Funding

This work was supported by the “Sapienza” University of Rome Grant 2015 (Prot. C26A158EEK).

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

WDTCWell-Differentiated Thyroid Cancers
PTCPapillary Thyroid Cancer
FTCFollicular Thyroid Cancer
PDTCPoorly Differentiated Thyroid Cancers
ATCAnaplastic Thyroid Cancer
FNACFine-Needle Aspiration Cytology
TNMTumor Node Metastasis
CTLCytotoxic T Lymphocytes
NKNatural Killer
PD-1Programmed Cell Death 1
TGF-TGF-βTransforming Growth Factor β
IL-10Interleukin 10
VEGFVascular Endothelial Growth Factor
CDCluster of Differentiation
CTLA-4Cytotoxic T-Lymphocyte Antigen 4
DFSDisease-free survival
DFIDisease-free interval
ORROverall response rate

References

  1. American Cancer Society, Inc. Available online: https://cancerstatisticscenter.cancer.org (accessed on 23 January 2019).
  2. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2019. CA Cancer J. Clin. 2019, 69, 7–34. [Google Scholar] [CrossRef] [PubMed]
  3. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Available online: https://seer.cancer.gov/statfacts/html/thyro.html (accessed on 23 January 2019).
  4. Nikiforov, Y.E.; Biddinger, P.W.; Thompson, L.D.R. Diagnostic Pathology and Molecular Genetics of the Thyroid; Lippincott Williams and Wilkins: Philadelphia, PA, USA, 2009. [Google Scholar]
  5. Tavares, C.; Melo, M.; Cameselle-Teijeiro, J.M.; Soares, P.; Sobrinho-Simões, M. Endocrine Tumours: Genetic predictors of thyroid cancer outcome. Eur. J. Endocrinol. 2016, 174, R117–R126. [Google Scholar] [CrossRef] [PubMed]
  6. Xu, B.; Ghossein, R. Genomic Landscape of poorly Differentiated and Anaplastic Thyroid Carcinoma. Endocr. Pathol. 2016, 27, 205–212. [Google Scholar] [CrossRef]
  7. Molinaro, E.; Romei, C.; Biagini, A.; Sabini, E.; Agate, L.; Mazzeo, S.; Materazzi, G.; Sellari-Franceschini, S.; Ribechini, A.; Torregrossa, L.; et al. Anaplastic thyroid carcinoma: From clinicopathology to genetics and advanced therapies. Nat. Rev. Endocrinol. 2017, 13, 644–660. [Google Scholar] [CrossRef]
  8. Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell 2014, 159, 676–690. [Google Scholar] [CrossRef] [PubMed]
  9. Elisei, R.; Ugolini, C.; Viola, D.; Lupi, C.; Biagini, A.; Giannini, R.; Romei, C.; Miccoli, P.; Pinchera, A.; Basolo, F. BRAFV600E mutation and outcome of patients with papillary thyroid carcinoma: A 15-year median follow-up study. J. Clin. Endocrinol. Metab. 2008, 93, 3943–3949. [Google Scholar] [CrossRef]
  10. Haugen, B.R.; Sawka, A.M.; Alexander, E.K.; Bible, K.C.; Caturegli, P.; Doherty, G.M.; Mandel, S.J.; Morris, J.C.; Nassar, A.; Pacini, F.; et al. American Thyroid Association Guidelines on the Management of Thyroid Nodules and Differentiated Thyroid Cancer Task Force Review and Recommendation on the Proposed Renaming of Encapsulated Follicular Variant Papillary Thyroid Carcinoma Without Invasion to Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features. Thyroid 2017, 27, 481–483. [Google Scholar] [CrossRef]
  11. Trimboli, P.; Virili, C.; Romanelli, F.; Crescenzi, A.; Giovanella, L. Galectin-3 Performance in Histologic a Cytologic Assessment of Thyroid Nodules: A Systematic Review and Meta-Analysis. Int. J. Mol. Sci. 2017, 18, 1756. [Google Scholar] [CrossRef]
  12. Nikiforov, Y.E. Role of molecular markers in thyroid nodule management: Then and now. Endocr. Pract. 2017, 23, 979–988. [Google Scholar] [CrossRef]
  13. Ulisse, S.; Bosco, D.; Nardi, F.; Nesca, A.; D’Armiento, E.; Guglielmino, V.; De Vito, C.; Sorrenti, S.; Pironi, D.; Tartaglia, F.; et al. Thyroid imaging reporting and data system score combined with the new italian classification for thyroid cytology improves the clinical management of indeterminate nodules. Int. J. Endocrinol. 2017, 2017, 9692304. [Google Scholar] [CrossRef]
  14. Amin, M.B.; Edge, S.; Greene, F.; Byrd, D.R.; Brookland, R.K.; Washington, M.K.; Gershenwald, J.E.; Compton, C.C.; Hess, K.R.; Sullivan, D.C.; et al. AJCC Cancer Staging Manual, 8th ed.; Springer: New York, NY, USA, 2017. [Google Scholar]
  15. Pacini, F.; Castagna, M.G.; Brilli, L.; Pentheroudakis, G. On behalf of the ESMO guidelines working group. Thyroid cancer: ESMO clinical practice guidelines for diagnosis treatment and follow-up. Ann. Oncol. 2012, 23, vii110–vii119. [Google Scholar] [CrossRef]
  16. Haugen, B.R. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: What is new and what has changed? Cancer 2017, 123, 372–381. [Google Scholar] [CrossRef] [PubMed]
  17. Smallridge, R.C.; Ain, K.B.; Asa, S.L.; Bible, K.C.; Brierley, J.D.; Burman, K.D.; Kebebew, E.; Lee, N.Y.; Nikiforov, Y.E.; Rosenthal, M.S.; et al. American Thyroid Association Anaplastic Thyroid Cancer Guidelines Taskforce. American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid 2012, 22, 1104–1139. [Google Scholar] [CrossRef]
  18. Tuccilli, C.; Baldini, E.; Arlot-Bonnemains, Y.; Chesnel, F.; Sorrenti, S.; De Vito, C.; D’Armiento, E.; Antonelli, A.; Fallahi, P.; Watutantrige, S.; et al. Expression and prognostic value of the cell polarity PAR complex members in thyroid cancer. Int. J. Oncol. 2017, 50, 1413–1422. [Google Scholar] [CrossRef] [PubMed]
  19. Baldini, E.; Tuccilli, C.; Arlot-Bonnemains, Y.; Chesnel, F.; Sorrenti, S.; De Vito, C.; Catania, A.; D’Armiento, E.; Antonelli, A.; Fallahi, P.; et al. Deregulated expression of VHL mRNA variants in papillary thyroid cancer. Mol. Cell. Endocrinol. 2017, 443, 121–127. [Google Scholar] [CrossRef]
  20. Ferrari, S.M.; Fallahi, P.; Politti, U.; Materazzi, G.; Baldini, E.; Ulisse, S.; Miccoli, P.; Antonelli, A. Molecular Targeted Therapies of Aggressive Thyroid Cancer. Front. Endocrinol. 2015, 6, 176. [Google Scholar] [CrossRef]
  21. Fallahi, P.; Ruffilli, I.; Elia, G.; Ragusa, F.; Ulisse, S.; Baldini, E.; Miccoli, M.; Materazzi, G.; Antonelli, A.; Ferrari, S.M. Novel treatment options for anaplastic thyroid cancer. Expert Rev. Endocrinol. Metab. 2017, 12, 279–288. [Google Scholar] [CrossRef]
  22. Lennon, P.; Deady, S.; Healy, M.L.; Toner, M.; Kinsella, J.; Timon, C.I.; O’Neill, J.P. Anaplastic thyroid carcinoma: Failure of conventional therapy but hope of targeted therapy. Head Neck 2016, 38 (Suppl. 1), E1122–E1129. [Google Scholar] [CrossRef]
  23. Baldini, E.; D’Armiento, M.; Ulisse, S. A new aurora in anaplastic thyroid cancer therapy. Int. J. Endocrinol. 2014, 2014, 816430. [Google Scholar] [CrossRef]
  24. Schreiber, R.D.; Old, L.J.; Smyth, M.J. Cancer immunoediting: Integrating immunity’s roles in cancer suppression and promotion. Science 2011, 331, 1565–1570. [Google Scholar] [CrossRef]
  25. Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674. [Google Scholar] [CrossRef] [PubMed]
  26. Ostrand-Rosenberg, S.; Sinha, P. Myeloid-derived suppressor cells: Linking inflammation and cancer. J. Immunol. 2009, 182, 4499–4506. [Google Scholar] [CrossRef] [PubMed]
  27. Mougiakakos, D.; Choudhury, A.; Kiessling, R.; Johansson, C.C. Regulatory T cells in cancer. Adv. Cancer Res. 2010, 107, 57–117. [Google Scholar] [CrossRef] [PubMed]
  28. Shields, J.D.; Kourtis, I.C.; Tomei, A.A.; Roberts, J.M.; Swartz, M.A. Induction of lymphoid-like stroma and immune escape by tumors that express the chemokine CCL21. Science 2010, 328, 749–752. [Google Scholar] [CrossRef] [PubMed]
  29. Yang, L.; Pang, Y.; Moses, H.L. TGF-beta and immune cells: An important regulatory axis in the tumor microenvironment and progression. Trends Immunol. 2010, 31, 220–227. [Google Scholar] [CrossRef] [PubMed]
  30. Pardoll, D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 2012, 12, 252–264. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  31. Henick, B.S.; Herbst, R.S.; Goldberg, S.B. The PD-1 pathway as a therapeutic target to overcome immune escape mechanisms in cancer. Expert Opin. Ther. Targets 2014, 18, 1407–1420. [Google Scholar] [CrossRef] [PubMed]
  32. La-Beck, N.M.; Jean, G.W.; Huynh, C.; Alzghari, S.K.; Lowe, D.B. Immune Checkpoint Inhibitors: New Insights and Current Place in Cancer Therapy. Pharmacotherapy 2015, 35, 963–976. [Google Scholar] [CrossRef]
  33. Liotti, F.; Prevete, N.; Vecchio, G.; Melillo, R.M. Recent advances in understanding immune phenotypes of thyroid carcinomas: Prognostication and emerging therapies. F1000Res 2019, 28, 8. [Google Scholar] [CrossRef]
  34. Bruno, T.C.; French, J.D.; Jordan, K.R.; Ramirez, O.; Sippel, T.R.; Borges, V.F.; Haugen, B.R.; McCarter, M.D.; Waziri, A.; Slansky, J.E. Influence of human immune cells on cancer: Studies at the University of Colorado. Immunol. Res. 2013, 55, 22–33. [Google Scholar] [CrossRef]
  35. French, J.D. Revisiting immune-based therapies for aggressive follicular cell-derived thyroid cancers. Thyroid 2013, 23, 529–542. [Google Scholar] [CrossRef] [PubMed]
  36. French, J.D.; Weber, Z.J.; Fretwell, D.L.; Said, S.; Klopper, J.P.; Haugen, B.R. Tumor-associated lymphocytes and increased FoxP3+ regulatory T cell frequency correlate with more aggressive papillary thyroid cancer. J. Clin. Endocrinol. Metab. 2010, 95, 2325–2333. [Google Scholar] [CrossRef]
  37. Angell, T.E.; Lechner, M.G.; Jang, J.K.; Correa, A.J.; LoPresti, J.S.; Epstein, A.L. BRAF V600E in papillary thyroid carcinoma is associated with increased programmed death ligand 1 expression and suppressive immune cell infiltration. Thyroid 2014, 24, 1385–1393. [Google Scholar] [CrossRef]
  38. Cunha, L.L.; Marcello, M.A.; Ward, L.S. The role of the inflammatory microenvironment in thyroid carcinogenesis. Endocr. Relat. Cancer 2014, 21, R85–R103. [Google Scholar] [CrossRef]
  39. Lewinski, A.; Sliwka, P.W.; Stasiolek, M. Dendritic cells in autoimmune disorders and cancer of the thyroid. Folia Histochem. Cytobiol. 2014, 52, 18–28. [Google Scholar] [CrossRef] [PubMed]
  40. Severson, J.J.; Serracino, H.S.; Mateescu, V.; Raeburn, C.D.; McIntyre, R.C.; Sams, S.B.; Haugen, B.R.; French, B.R. PD-1+Tim-3+ CD8+ T Lymphocytes Display Varied Degrees of Functional Exhaustion in Patients with Regionally Metastatic Differentiated Thyroid Cancer. Cancer Immunol. Res. 2015, 3, 620–630. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  41. Bastman, J.J.M.; Serracinom, H.S.; Zhu, Y.; Koenig, M.R.; Mateescu, V.; Sams, S.B.; Davies, K.D.; Raeburn, C.D.; McIntyre, R.C., Jr.; Haugen, B.R.; et al. Tumor-Infiltrating T Cells and the PD-1 Checkpoint Pathway in Advanced Differentiated and Anaplastic Thyroid Cancer. J. Clin. Endocrinol. Metab. 2016, 101, 2863–2873. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Cunha, L.L.; Marcello, M.A.; Morari, E.C.; Nonogaki, S.; Conte, F.F.; Gerhard, R.; Soares, F.A.; Vassallo, J.; Ward, L.S. Differentiated thyroid carcinomas may elude the immune system by B7H1 up-regulation. Endocr. Relat. Cancer 2013, 20, 103–110. [Google Scholar] [CrossRef]
  43. Chowdhury, S.; Veyhl, J.; Jessa, F.; Polyakova, O.; Alenzi, A.; MacMillan, C.; Ralhan, R.; Walfish, P.G. Programmed death-ligand 1 overexpression is a prognostic marker for aggressive papillary thyroid cancer and its variants. Oncotarget 2016, 7, 32318–32328. [Google Scholar] [CrossRef] [Green Version]
  44. Ahn, S.; Kim, T.H.; Kim, S.W.; Ki, C.S.; Jang, H.W.; Kim, J.S.; Kim, J.H.; Choe, J.H.; Shin, J.H.; Hahn, S.Y.; et al. Comprehensive screening for PD-L1 expression in thyroid cancer. Endocr. Relat. Cancer 2017, 24, 97–106. [Google Scholar] [CrossRef]
  45. Shi, R.L.; Qu, N.; Luo, T.X.; Xiang, J.; Liao, T.; Sun, G.H.; Wang, Y.; Wang, Y.L.; Huang, C.P.; Ji, Q.H. Programmed death-ligand 1 expression in papillary thyroid cancer and its correlation with clinicopathologic factors and recurrence. Thyroid 2017, 27, 537–545. [Google Scholar] [CrossRef] [PubMed]
  46. Zwaenepoel, K.; Jacobs, J.; De Meulenaere, A.; Silence, K.; Smits, E.; Siozopoulou, V.; Hauben, E.; Rolfo, C.; Rottey, S.; Pauwels, P. CD70 and PD-L1 in anaplastic thyroid cancer—Promising targets for immunotherapy. Histopathology 2017, 71, 357–365. [Google Scholar] [CrossRef] [PubMed]
  47. Lahat, N.; Rahat, M.A.; Sadeh, O.; Kinarty, A.; Kraiem, Z. Regulation of HLA-DR and costimulatory B7 molecules in human thyroid carcinoma cells: Differential binding of transcription factors to the HLA-DRalpha promoter. Thyroid 1998, 8, 361–369. [Google Scholar] [CrossRef] [PubMed]
  48. Battifora, M.; Pesce, G.; Paolieri, F.; Fiorino, N.; Giordano, C.; Riccio, A.M.; Torre, G.; Olive, D.; Bagnasco, M. B7.1 costimulatory molecule is expressed on thyroid follicular cells in Hashimoto’s thyroiditis, but not in Graves’ disease. J. Clin. Endocrinol. Metab. 1998, 83, 4130–4139. [Google Scholar] [CrossRef]
  49. Shah, R.; Banks, K.; Patel, A.; Dogra, S.; Terrell, R.; Powers, P.A.; Fenton, C.; Dinauer, C.A.; Tuttle, R.M.; Francis, G.L. Intense expression of the b7-2 antigen presentation coactivator is an unfavorable prognostic indicator for differentiated thyroid carcinoma of children and adolescents. J. Clin. Endocrinol. Metab. 2002, 87, 4391–4397. [Google Scholar] [CrossRef] [PubMed]
  50. Xu, W.C.; Li, Z.B.; Chen, Y.R.; Li, X.T.; Huang, J.X.; Li, Y.G.; Chen, S.R. Expression and distribution of S-100, CD83, and costimulatory molecules (CD80 and CD86) in tissues of thyroid papillary carcinoma. Cancer Investig. 2011, 29, 286–292. [Google Scholar] [CrossRef] [PubMed]
  51. Yin, M.; Di, G.; Bian, M. Dysfunction of natural killer cells mediated by PD-1 and Tim-3 pathway in anaplastic thyroid cancer. Int. Immunopharmacol. 2018, 64, 333–339. [Google Scholar] [CrossRef] [PubMed]
  52. Na, K.J.; Choi, H. Immune landscape of papillary thyroid cancer and immunotherapeutic implications. Endocr. Relat. Cancer 2018, 25, 523–531. [Google Scholar] [CrossRef]
  53. Shinohara, T.; Taniwaki, M.; Ishida, Y.; Kawaichi, M.; Honjo, T. Structure and chromosomal localization of the human PD-1 gene (PDCD1). Genomics 1994, 23, 704–706. [Google Scholar] [CrossRef]
  54. Ishida, Y.; Agata, Y.; Shibahara, K.; Honjo, T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992, 11, 3887–3895. [Google Scholar] [CrossRef] [PubMed]
  55. Riella, L.V.; Paterson, A.M.; Sharpe, A.H.; Chandraker, A. Role of PD-1 pathway in the immune response. Am. J. Transplant. 2012, 12, 2575–2587. [Google Scholar] [CrossRef] [PubMed]
  56. Zamani, M.R.; Aslani, S.; Salmaninejad, A.; Javan, M.R.; Rezaei, N. PD-1/PD-L and autoimmunity: A growing relationship. Cell. Immunol. 2016, 310, 27–41. [Google Scholar] [CrossRef] [PubMed]
  57. Bardhan, K.; Anagnostou, T.; Boussiotis, V.A. The PD1:PD-L1/2 Pathway from Discovery to Clinical Implementation. Front. Immunol. 2016, 7, 550. [Google Scholar] [CrossRef] [PubMed]
  58. Lin, H.Y.; Tang, H.Y.; Davis, F.B.; Davis, P.J. Resveratrol and apoptosis. Ann. N. Y. Acad. Sci. 2011, 1215, 79–88. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  59. Chin, Y.T.; Wei, P.L.; Ho, Y.; Nana, A.W.; Changou, C.A.; Chen, Y.R.; Yang, Y.S.; Hsieh, M.T.; Hercbergs, A.; Davis, P.J.; et al. Thyroxine inhibits resveratrol-caused apoptosis by PD-L1 in ovarian cancer cells. Endocr. Relat. Cancer 2018, 25, 533–545. [Google Scholar] [CrossRef] [PubMed]
  60. Lin, H.Y.; Chin, Y.T.; Nana, A.W.; Shih, Y.J.; Lai, H.Y.; Tang, H.Y.; Leinung, M.; Mousa, S.A.; Davis, P.J. Actions of l-thyroxine and Nano-diamino-tetrac (Nanotetrac) on PD-L1 in cancer cells. Steroids 2016, 114, 59–67. [Google Scholar] [CrossRef] [PubMed]
  61. Wu, H.; Sun, Y.; Ye, H.; Yang, S.; Lee, S.L.; de las Morenas, A. Anaplastic thyroid cancer: Outcome and the mutation/expression profiles of potential targets. Pathol. Oncol. Res. 2015, 21, 695–701. [Google Scholar] [CrossRef]
  62. Bai, Y.; Niu, D.; Huang, X.; Jia, L.; Kang, Q.; Dou, F.; Ji, X.; Xue, W.; Liu, Y.; Li, Z.; et al. PD-L1 and PD-1 expression are correlated with distinctive clinicopathological features in papillary thyroid carcinoma. Diagn. Pathol. 2017, 12, 72. [Google Scholar] [CrossRef]
  63. cBioportal. Available online: http://www.cbioportal.org (accessed on 14 February 2019).
  64. Tuccilli, C.; Baldini, E.; Sorrenti, S.; Catania, A.; Antonelli, A.; Fallahi, P.; Tartaglia, F.; Barollo, S.; Mian, C.; Palmieri, A.; et al. CTLA-4 and PD-1 Ligand Gene Expression in Epithelial Thyroid Cancers. Int. J. Endocrinol. 2018, 2018, 1742951. [Google Scholar] [CrossRef]
  65. Rosenbaum, M.W.; Gigliotti, B.J.; Pai, S.I.; Parangi, S.; Wachtel, H.; Mino-Kenudson, M.; Gunda, V.; Faquin, W.C. PD-L1 and IDO1 Are Expressed in Poorly Differentiated Thyroid Carcinoma. Endocr. Pathol. 2018, 29, 59–67. [Google Scholar] [CrossRef]
  66. Aghajani, M.J.; Yang, T.; McCafferty, C.E.; Graham, S.; Wu, X.; Niles, N. Predictive relevance of programmed cell death protein 1 and tumor-infiltrating lymphocyte expression in papillary thyroid cancer. Surgery 2018, 163, 130–136. [Google Scholar] [CrossRef]
  67. Bai, Y.; Guo, T.; Huang, X.; Wu, Q.; Niu, D.; Ji, X.; Feng, Q.; Li, Z.; Kakudo, K. In papillary thyroid carcinoma, expression by immunohistochemistry of BRAF V600E, PD-L1, and PD-1 is closely related. Virchows Arch. 2018, 472, 779–787. [Google Scholar] [CrossRef]
  68. Chintakuntlawar, A.V.; Rumilla, K.M.; Smith, C.Y.; Jenkins, S.M.; Foote, R.L.; Kasperbauer, J.L.; Morris, J.C.; Ryder, M.; Alsidawi, S.; Hilger, C.; et al. Expression of PD-1 and PD-L1 in Anaplastic Thyroid Cancer Patients Treated With Multimodal Therapy: Results From a Retrospective Study. J. Clin. Endocrinol. Metab. 2017, 102, 1943–1950. [Google Scholar] [CrossRef]
  69. Fu, G.; Polyakova, O.; MacMillan, C.; Ralhan, R.; Walfish, P.G. Programmed Death—Ligand 1 Expression Distinguishes Invasive Encapsulated Follicular Variant of Papillary Thyroid Carcinoma from Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features. EBioMedicine 2017, 18, 50–55. [Google Scholar] [CrossRef]
  70. Rossi, E.D.; Martini, M. New Insight in a New Entity: NIFTPS and Valuable Role of Ancillary Techniques. The Role of PD-L1. EBioMedicine 2017, 18, 11–12. [Google Scholar] [CrossRef]
  71. Hsieh, A.M.; Polyakova, O.; Fu, G.; Chazen, R.S.; MacMillan, C.; Witterick, I.J.; Ralhan, R.; Walfish, P.G. Programmed death-ligand 1 expression by digital image analysis advances thyroid cancer diagnosis among encapsulated follicular lesions. Oncotarget 2018, 9, 19767–19782. [Google Scholar] [CrossRef] [Green Version]
  72. Nikiforov, Y.E.; Seethala, R.R.; Tallini, G.; Baloch, Z.W.; Basolo, F.; Thompson, L.D.; Barletta, J.A.; Wenig, B.M.; Al Ghuzlan, A.; Kakudo, K.; et al. Nomenclature Revision for Encapsulated Follicular Variant of Papillary Thyroid Carcinoma: A Paradigm Shift to Reduce Overtreatment of Indolent Tumors. JAMA Oncol. 2016, 2, 1023–1029. [Google Scholar] [CrossRef]
  73. Maletta, F.; Massa, F.; Torregrossa, L.; Duregon, E.; Casadei, G.P.; Basolo, F.; Tallini, G.; Volante, M.; Nikiforov, Y.E.; Papotti, M. Cytological features of “noninvasive follicular thyroid neoplasm with papillary-like nuclear features” and their correlation with tumor histology. Hum. Pathol. 2016, 54, 134–142. [Google Scholar] [CrossRef]
  74. Bizzarro, T.; Martini, M.; Capodimonti, S.; Straccia, P.; Lombardi, C.P.; Pontecorvi, A.; Larocca, L.M.; Rossi, E.D. Young investigator challenge: The morphologic analysis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features on liquid-based cytology: Some insights into their identification. Cancer Cytopathol. 2016, 124, 699–710. [Google Scholar] [CrossRef] [Green Version]
  75. Patel, S.P.; Kurzrock, R. PD-L1 Expression as a Predictive Biomarker in Cancer Immunotherapy. Mol. Cancer Ther. 2015, 14, 847–856. [Google Scholar] [CrossRef] [Green Version]
  76. Garon, E.B.; Rizvi, N.A.; Hui, R.; Leighl, N.; Balmanoukian, A.S.; Eder, J.P.; Patnaik, A.; Aggarwal, C.; Gubens, M.; Horn, L.; et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 2015, 372, 2018–2028. [Google Scholar] [CrossRef]
  77. Hui, R.; Garon, E.B.; Goldman, J.W.; Leighl, N.B.; Hellmann, M.D.; Patnaik, A.; Gandhi, L.; Eder, J.P.; Ahn, M.J.; Horn, L.; et al. Pembrolizumab as first-line therapy for patients with PD-L1-positive advanced non-small cell lung cancer: A phase 1 trial. Ann. Oncol. 2017, 28, 874–881. [Google Scholar] [CrossRef]
  78. Brauner, E.; Gunda, V.; Vanden Borre, P.; Zurakowski, D.; Kim, Y.S.; Dennett, K.V.; Amin, S.; Freeman, G.J.; Parangi, S. Combining BRAF inhibitor and anti PD-L1 antibody dramatically improves tumor regression and anti tumor immunity in an immunocompetent murine model of anaplastic thyroid cancer. Oncotarget 2016, 7, 17194–17211. [Google Scholar] [CrossRef] [Green Version]
  79. Aghajani, M.; Graham, S.; McCafferty, C.; Shaheed, C.A.; Roberts, T.; DeSouza, P.; Yang, T.; Niles, N. Clinicopathologic and Prognostic Significance of Programmed Cell Death Ligand 1 Expression in Patients with Non-Medullary Thyroid Cancer: A Systematic Review and Meta-Analysis. Thyroid 2018, 28, 349–361. [Google Scholar] [CrossRef]
  80. Pozdeyev, N.; Gay, L.M.; Sokol, E.S.; Hartmaier, R.; Deaver, K.E.; Davis, S.; French, J.D.; Borre, P.V.; LaBarbera, D.V.; Tan, A.C.; et al. Genetic Analysis of 779 Advanced Differentiated and Anaplastic Thyroid Cancers. Clin. Cancer Res. 2018, 24, 3059–3068. [Google Scholar] [CrossRef]
  81. Antonelli, A.; Ferrari, S.M.; Fallahi, P. Current and future immunotherapies for thyroid cancer. Expert Rev. Anticancer Ther. 2018, 18, 149–159. [Google Scholar] [CrossRef]
  82. Constantinidou, A.; Alifieris, C.; Trafalis, D.T. Targeting programmed cell death-1(PD-1) and ligand (PD-L1): A new era in cancer active immunotherapy. Pharmacol. Ther. 2018, 194, 84–106. [Google Scholar] [CrossRef]
  83. Romano, E.; Romero, P. The therapeutic promise of disrupting the PD-1/PD-L1 immune checkpoint in cancer: Unleashing the CD8 T cell mediated anti-tumor activity results in significant, unprecedented clinical efficacy in various solid tumors. J. Immunother. Cancer 2015, 3, 15. [Google Scholar] [CrossRef]
  84. Herbst, R.S.; Soria, J.C.; Kowanetz, M.; Fine, G.D.; Hamid, O.; Gordon, M.S.; Sosman, J.A.; McDermott, D.F.; Powderly, J.D.; Gettinger, S.N.; et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014, 515, 563–567. [Google Scholar] [CrossRef] [Green Version]
  85. Powles, T.; Eder, J.P.; Fine, G.D.; Braiteh, F.S.; Loriot, Y.; Cruz, C.; Bellmunt, J.; Burris, H.A.; Petrylak, D.P.; Teng, S.L.; et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 2014, 515, 558–562. [Google Scholar] [CrossRef]
  86. Tumeh, P.C.; Harview, C.L.; Yearley, J.H.; Shintaku, I.P.; Taylor, E.J.; Robert, L.; Chmielowski, B.; Spasic, M.; Henry, G.; Ciobanu, V.; et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014, 515, 568–571. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Kim, K.; Jeon, S.; Kim, T.M.; Jung, C.K. Immune Gene Signature Delineates a Subclass of Papillary Thyroid Cancer with Unfavorable Clinical Outcomes. Cancers 2018, 10, 494. [Google Scholar] [CrossRef] [PubMed]
  88. Gunda, V.; Gigliotti, B.; Ashry, T.; Ndishabandi, D.; McCarthy, M.; Zhou, Z.; Amin, S.; Lee, K.E.; Stork, T.; Wirth, L.; et al. Anti-PD-1/PD-L1 therapy augments lenvatinib’s efficacy by favorably altering the immune microenvironment of murine anaplastic thyroid cancer. Int. J. Cancer 2018. [Google Scholar] [CrossRef] [PubMed]
  89. Cantara, S.; Bertelli, E.; Occhini, R.; Regoli, M.; Brilli, L.; Pacini, F.; Castagna, M.G.; Toti, P. Blockade of the programmed death ligand 1 (PD-L1) as potential therapy for anaplastic thyroid cancer. Endocrine 2019. [Google Scholar] [CrossRef] [PubMed]
  90. Kollipara, R.; Schneider, B.; Radovich, M.; Babu, S.; Kiel, P.J. Exceptional Response with Immunotherapy in a Patient with Anaplastic Thyroid Cancer. Oncologist 2017, 22, 1149–1151. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  91. Iyer, P.C.; Dadu, R.; Gule-Monroe, M.; Busaidy, N.L.; Ferrarotto, R.; Habra, M.A.; Zafereo, M.; Williams, M.D.; Gunn, B.; Grosu, H.; et al. Salvage pembrolizumab added to kinase inhibitor therapy for the treatment of anaplastic thyroid carcinoma. J. Immunother. Cancer 2018, 6, 68. [Google Scholar] [CrossRef]
  92. Mehnert, J.M.; Varga, A.; Brose, M.S.; Aggarwal, R.R.; Lin, C.C.; Prawira, A.; de Braud, F.; Tamura, K.; Doi, T.; Piha-Paul, S.A.; et al. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with advanced, PD-L1-positive papillary or follicular thyroid cancer. BMC Cancer 2019, 19, 196. [Google Scholar] [CrossRef]
  93. Clinical Trials.gov. Available online: https://clinicaltrials.gov/ct2/show/NCT02688608 (accessed on 18 February 2019).
  94. Naoum, G.E.; Morkos, M.; Kim, B.; Arafat, W. Novel targeted therapies and immunotherapy for advanced thyroid cancers. Mol. Cancer 2018, 17, 51. [Google Scholar] [CrossRef]
  95. Chen, M.L.; Yan, B.S.; Lu, W.C.; Chen, M.H.; Yu, S.L.; Yang, P.C.; Cheng, A.L. Sorafenib relieves cell-intrinsic and cell-extrinsic inhibitions of effector T cells in tumor microenvironment to augment antitumor immunity. Int. J. Cancer 2014, 134, 319–331. [Google Scholar] [CrossRef]
  96. Ferrari, S.M.; Bocci, G.; Di Desidero, T.; Elia, G.; Ruffilli, I.; Ragusa, F.; Orlandi, P.; Paparo, S.R.; Patrizio, A.; Piaggi, S.; et al. Lenvatinib exhibits antineoplastic activity in anaplastic thyroid cancer in vitro and in vivo. Oncol. Rep. 2018, 39, 2225–2234. [Google Scholar] [CrossRef]
  97. Clinical Trials.gov. Available online: https://clinicaltrials.gov/ct2/show/NCT02501096 (accessed on 6 March 2019).
Ijms 20 01405 g001 550
Figure 1. Inhibitory effect of the immune checkpoint receptors CTLA4 and PD-1 on T cell activation. T-cell activation depends on two simultaneous signals: a) interaction of the T-cell receptor with the complex MHC-antigenic peptides; b) co-stimulation by CD28 binding to CD80/CD86. The alternative ligation of CD80/CD86 to CTLA4, as well as the interaction between PD-1 and PD-L1/L2, lead to T-cell exhaustion. TCR, T cell receptor; MHC-I, major histocompatibility complex class I; CTLA-4, Cytotoxic T-Lymphocyte Antigen 4; PD-1, programmed cell death 1; PD-L1/2, PD-1 ligand 1 and 2; APC, Antigen presenting cells.
Figure 1. Inhibitory effect of the immune checkpoint receptors CTLA4 and PD-1 on T cell activation. T-cell activation depends on two simultaneous signals: a) interaction of the T-cell receptor with the complex MHC-antigenic peptides; b) co-stimulation by CD28 binding to CD80/CD86. The alternative ligation of CD80/CD86 to CTLA4, as well as the interaction between PD-1 and PD-L1/L2, lead to T-cell exhaustion. TCR, T cell receptor; MHC-I, major histocompatibility complex class I; CTLA-4, Cytotoxic T-Lymphocyte Antigen 4; PD-1, programmed cell death 1; PD-L1/2, PD-1 ligand 1 and 2; APC, Antigen presenting cells.
Ijms 20 01405 g001
Table
Table 1. Association of PD-L1 protein levels with clinico-pathological features and BRAF mutational status in thyroid cancer patients. ETI, extra-thyroidal invasion; DTC, differentiated thyroid cancer; PTC, papillary thyroid cancer; ATC, anaplastic thyroid cancer; FTC, follicular thyroid cancer; PDTC, poorly differentiated thyroid cancer; --, non-evaluated; DFS, disease-free survival; MAB, monoclonal antibody; PAB polyclonal antibody.
Table 1. Association of PD-L1 protein levels with clinico-pathological features and BRAF mutational status in thyroid cancer patients. ETI, extra-thyroidal invasion; DTC, differentiated thyroid cancer; PTC, papillary thyroid cancer; ATC, anaplastic thyroid cancer; FTC, follicular thyroid cancer; PDTC, poorly differentiated thyroid cancer; --, non-evaluated; DFS, disease-free survival; MAB, monoclonal antibody; PAB polyclonal antibody.
Correlations/Associations
AntibodiesAgeGenderTNMStageMultifocalityETIDFSBRAFV600E
Ref. No.Case StudyPD-L1 ExpressionHost-TypeClone (Source)
[42]407 patients, Including 293 DTCIncreased levels in DTC vs. benign lesionsRabbit PABAb82059 (Abcam)NoNoNoNoNoNoNoNo----
[37]33 PTCIncreased levels in BRAFV600E vs. BRAFwt PTCRabbit PAB4059 (ProSci)------------------Yes
[61]13 ATCPositive in 23% of ATC patientsMouse MAB5H1 (non-commercial)--------------------
[43]251 patients including 185 PTCIncreased in PTC vs. benign lesionsRabbit MABE1L3N (Cell Signaling)----------NoNoNoYes--
[41]92 DTC; 22 patients with advanced DTC/ATCPositive in 64% of DTC and 59.1% of advanced DTC/ATCRabbit MABSP142 (Spring Bioscience)----NoYes----------No
[44]407 thyroid cancersPositive in 6.1% of PTC, 7.6% of FTC, 22.2% of ATCRabbit MABSP142 (Spring Bioscience)NoNoNoNoNoNoNoNoNoNo
[45]260 PTC and normal matched tissuesIncreased in 52.3% of PTC vs. normal tissueRabbit MABAb174838 (Abcam)NoNoNoNo----YesYesYes--
[62]126 PTCPositive in 53.2% of PTCRabbit MABSP142 (Spring Bioscience)NoYesNoNo--NoNo----No
[46]49 ATCPositive in 28.6% of ATCRabbit MABE1L3N (Cell Signaling)------------------No
[68]16 ATCPositive in 81.3% of ATCRabbit MABE1L3N (Cell Signaling)NoNo------No----No--
[66]75 PTCPositive in 66.7% of PTCMouse MAB22C3 (DAKO)NoNoNoNo--NoNoYesNo--
[65]28 PDTCPositive in 25% of PDTCRabbit MABE1L3N (Cell Signaling)NoNoYes--NoNoYesNoNo--
[67]110 PTCPositive in 46% of PTCRabbit MABSP142 (Spring Bioscience)NoNoNoNo--NoNo----Yes
Table
Table 2. Association of PD-L1 mRNA levels with clinico-pathological features and BRAF mutational status in thyroid cancer patients. ETI, extra-thyroidal invasion; DTC, differentiated thyroid cancer; PTC, papillary thyroid cancer; ATC, anaplastic thyroid cancer; --, non-evaluated; DFS, disease-free survival.
Table 2. Association of PD-L1 mRNA levels with clinico-pathological features and BRAF mutational status in thyroid cancer patients. ETI, extra-thyroidal invasion; DTC, differentiated thyroid cancer; PTC, papillary thyroid cancer; ATC, anaplastic thyroid cancer; --, non-evaluated; DFS, disease-free survival.
Correlations/Associations
AgeGenderTNMStageMultifocalityETIDFSBRAFV600E
Ref. No.Case StudyPD-L1 mRNA Expression
[42]407 patients, Including 293 DTCIncreased levels in DTC vs. benign lesionsYesNoNoNoNoYesNoNo----
[63]482 PTC and 58 normal tissuesUnvaried in PTC vs. normal tissuesNoYesNoYesNoNo--YesYesYes
[41]92 DTC; 22 advanced DTC/ATCPositivity in 64% of DTC and 59.1% of advanced DTC/ATC----NoYes----------No
[64]94 PTC and normal matched tissues, 11 ATCIncreased in 46.8% of PTC and 27.3% of ATCNoNoNoNo--No----YesYes
Table
Table 3. FDA approved PD-1/PD-L1 inhibitors. HNSCC, head and neck squamous cell carcinoma; NSCLC, non-small cell lung cancer; cHL, classical Hodgkin lymphoma; MSI-H, microsatellite instability-high; PMBCL, primary mediastinal large B-cell lymphoma; HCC, hepatocellular carcinoma; SCCHN, squamous cell carcinoma of the head and neck; RCC, renal cell carcinoma; SCLC, small cell lung cancer; CSCC, cutaneous squamous cell carcinoma. Source: www.fda.gov.
Table 3. FDA approved PD-1/PD-L1 inhibitors. HNSCC, head and neck squamous cell carcinoma; NSCLC, non-small cell lung cancer; cHL, classical Hodgkin lymphoma; MSI-H, microsatellite instability-high; PMBCL, primary mediastinal large B-cell lymphoma; HCC, hepatocellular carcinoma; SCCHN, squamous cell carcinoma of the head and neck; RCC, renal cell carcinoma; SCLC, small cell lung cancer; CSCC, cutaneous squamous cell carcinoma. Source: www.fda.gov.
NameCommercial Name (Company)IgG IsotypeTargetFDA Approval
YearCancer Type
PembrolizumabKeytruda (Merck)IgG4PD-12014Melanoma
2016HNSCC, NSCLC
2017Gastric/gastroesophageal adenocarcinoma, cHL, urothelial carcinoma, MSI-H cancers
2018Merkel cell carcinoma, PMBCL, HCC, cervical cancer
NivolumabOpdivo (Bristol-Myers Squibb)IgG4PD-12014Melanoma, NSCLC
2016SCCHN, cHL
2017Urothelial carcinoma, HCC, MSI-H colorectal cancer
2018RCC, SCLC
Cemiplimab-rwlcLibtayo (Regeneron Pharmaceuticals)IgG4PD-12018CSCC
AtezolizumabTecentriq (Genentech Oncology)IgG1PD-L12016NSCLC, urothelial carcinoma
AvelumabBavencio (EMD Serono)IgG1PD-L12017Merkel cell carcinoma, urothelial carcinoma
DurvalumabImfinzi (AstraZeneca)IgG1kPD-L12017Urothelial carcinoma
2018NSCLC

Share and Cite

MDPI and ACS Style

Ulisse, S.; Tuccilli, C.; Sorrenti, S.; Antonelli, A.; Fallahi, P.; D’Armiento, E.; Catania, A.; Tartaglia, F.; Amabile, M.I.; Giacomelli, L.; et al. PD-1 Ligand Expression in Epithelial Thyroid Cancers: Potential Clinical Implications. Int. J. Mol. Sci. 2019, 20, 1405. https://doi.org/10.3390/ijms20061405

AMA Style

Ulisse S, Tuccilli C, Sorrenti S, Antonelli A, Fallahi P, D’Armiento E, Catania A, Tartaglia F, Amabile MI, Giacomelli L, et al. PD-1 Ligand Expression in Epithelial Thyroid Cancers: Potential Clinical Implications. International Journal of Molecular Sciences. 2019; 20(6):1405. https://doi.org/10.3390/ijms20061405

Chicago/Turabian Style

Ulisse, Salvatore, Chiara Tuccilli, Salvatore Sorrenti, Alessandro Antonelli, Poupak Fallahi, Eleonora D’Armiento, Antonio Catania, Francesco Tartaglia, Maria Ida Amabile, Laura Giacomelli, and et al. 2019. "PD-1 Ligand Expression in Epithelial Thyroid Cancers: Potential Clinical Implications" International Journal of Molecular Sciences 20, no. 6: 1405. https://doi.org/10.3390/ijms20061405

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop