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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 May 2019) | Viewed by 46117

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Prof. Dr. Yoshihiro Hayakawa

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Guest Editor

Division of Pathogenic Biochemistry, Department of Bioscience, Institute of Natural Medicine, University of Toyama, Toyama, Japan
Interests: NK cell; innate immunity; cancer; metastasis; tumor microenvironment; anti-tumor immunity; inflammation

Special Issue Information

Dear Colleagues,

It has been widely recognized that cancerous cells require not only intrinsic oncogenic driver events, but also cross-talk with surrounding stromal cells for tumor development. Immune cells are one of the major component of tumor storma, therefore better understanding of the immunological tumor microenvironment is clearly important for developing effective cancer therapy. Success in recent immunotherapies of cancer by unleashing anti-tumor immunity with immune-checkpoint inhibitors, or using chimeric antigen receptor (CAR)-T cells have been emerging. However, a substantial proportion of patients show primary and/or adaptive resistance to immunotherapies. While a host immune response contributes to cancer eradication by its “bright side” of anti-tumor function, it is also involved in a selection and/or generation of cancer immune-escape by its “dark side” of pro-tumor function. By enhancing its beneficial anti-tumor actions along with limiting pro-tumor actions, we can be more confident in establishing promising cancer immunotherapy.

In this Special Issue, we will focus on the recent advances in cancer immunology and immunotherapy. Specifically, the studies on regulation of both “bright” and “dark” side of immunity in tumor microenvironment, and further modulation of immunological microenvironment or anti-tumor immune responses will be discussed.

Prof. Dr. Yoshihiro Hayakawa
Guest Editor

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Keywords

cancer
immunity
immunotherapy
antigen
antibody
cytokine
inflammation
microenvironment
chemokine
immune-escape
resistance

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Published Papers (7 papers)

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Research

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12 pages, 3610 KiB

Open AccessArticle

High Numbers and Densities of PD1⁺ T-Follicular Helper Cells in Triple-Negative Breast Cancer Draining Lymph Nodes Are Associated with Lower Survival

by Peter Bronsert, Anna von Schoenfeld, Jose Villacorta Hidalgo, Stefan Kraft, Jens Pfeiffer, Thalia Erbes, Martin Werner and Maximilian Seidl

Int. J. Mol. Sci. 2020, 21(17), 5948; https://doi.org/10.3390/ijms21175948 - 19 Aug 2020

Cited by 3 | Viewed by 2604

Abstract

Breast cancer tumor draining lymph nodes (TDLNs) display distinct morphologic changes depending on the breast cancer subtype. For triple-negative breast cancers (TNBC), draining LNs display a higher amount of secondary lymphoid follicles, which can be regarded as a surrogate marker for an activated humoral immune response. In the present study, we focus on PD1⁺ T-follicular helper cells (Tfh) in TDLNs of TNBC, since PD1⁺ Tfh are drivers of the germinal center (GC) reaction. We quantified PD1⁺ Tfh in 22 sentinel LNs with 853 GCs and interfollicular areas from 19 patients with TNBC by morphometry from digitalized immunostained tissue sections. Overall survival was significantly worse for patients with a higher number and area density of PD1⁺ Tfh within GCs of TDLNs. Further, we performed T-cell receptor gamma chain (TRG) analysis from microdissected tissue in the primary tumor and TDLNs. Eleven patients showed the same TRG clones in the tumor and the LN. Five patients shared the same TRG clones in the tumor and the GCs. In two patients, those clones were highly enriched inside the GCs. Enrichment of identical TRG clones at the tumor site vs. the TDLN was associated with improved overall survival. TDLNs are important relays of cancer immunity and enable surrogate approaches to predict the outcome of TNBC itself. Full article

(This article belongs to the Special Issue Cancer Immunology and Immunotherapy)

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21 pages, 2466 KiB

Open AccessArticle

Experimental Combined Immunotherapy of Tumours with Major Histocompatibility Complex Class I Downregulation

by Adrianna Grzelak, Ingrid Polakova, Jana Smahelova, Julie Vackova, Lucie Pekarcikova, Ruth Tachezy and Michal Smahel

Int. J. Mol. Sci. 2018, 19(11), 3693; https://doi.org/10.3390/ijms19113693 - 21 Nov 2018

Cited by 5 | Viewed by 4462

Abstract

Combined immunotherapy constitutes a novel, advanced strategy in cancer treatment. In this study, we investigated immunotherapy in the mouse TC-1/A9 model of human papillomavirus type 16 (HPV16)-associated tumors characterized by major histocompatibility complex class I (MHC-I) downregulation. We found that the induction of a significant anti-tumor response required a combination of DNA vaccination with the administration of an adjuvant, either the synthetic oligodeoxynucleotide ODN1826, carrying immunostimulatory CpG motifs, or α-galactosylceramide (α-GalCer). The most profound anti-tumor effect was achieved when these adjuvants were applied in a mix with a one-week delay relative to DNA immunization. Combined immunotherapy induced tumor infiltration with various subsets of immune cells contributing to tumor regression, of which cluster of differentiation (CD) 8⁺ T cells were the predominant subpopulation. In contrast, the numbers of tumor-associated macrophages (TAMs) were not markedly increased after immunotherapy but in vivo and in vitro results showed that they could be repolarized to an anti-tumor M1 phenotype. A blockade of T cell immunoglobulin and mucin-domain containing-3 (Tim-3) immune checkpoint had a negligible effect on anti-tumor immunity and TAMs repolarization. Our results demonstrate a benefit of combined immunotherapy comprising the activation of both adaptive and innate immunity in the treatment of tumors with reduced MHC-I expression. Full article

(This article belongs to the Special Issue Cancer Immunology and Immunotherapy)

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15 pages, 1774 KiB

Open AccessArticle

The Generation of CAR-Transfected Natural Killer T Cells for the Immunotherapy of Melanoma

by Bianca Simon, Manuel Wiesinger, Johannes März, Kilian Wistuba-Hamprecht, Benjamin Weide, Beatrice Schuler-Thurner, Gerold Schuler, Jan Dörrie and Ugur Uslu

Int. J. Mol. Sci. 2018, 19(8), 2365; https://doi.org/10.3390/ijms19082365 - 11 Aug 2018

Cited by 59 | Viewed by 7027

Abstract

Natural killer T (NKT) cells represent a cell subpopulation that combines characteristics of natural killer (NK) cells and T cells. Through their endogenous T-cell receptors (TCRs), they reveal a pronounced intrinsic anti-tumor activity. Thus, a NKT cell transfected with a chimeric antigen receptor (CAR), which recognizes a tumor-specific surface antigen, could attack tumor cells antigen-specifically via the CAR and additionally through its endogenous TCR. NKT cells were isolated from peripheral blood mononuclear cells (PBMCs), expanded, and electroporated with mRNA encoding a chondroitin sulfate proteoglycan 4 (CSPG4)-specific CAR. The CAR expression on NKT cells and their in vitro functionality were analyzed. A transfection efficiency of more than 80% was achieved. Upon stimulation with melanoma cells, CAR-NKT cells produced cytokines antigen-specifically. Compared with conventional CAR-T cells, cytokine secretion of CAR-NKT cells was generally lower. Specific cytotoxicity, however, was similar with CAR-NKT cells showing a trend towards improved cytotoxicity. Additionally, CAR-NKT cells could kill target cells through their endogenous TCRs. In summary, it is feasible to generate CAR-NKT cells by using mRNA electroporation. Their CAR-mediated cytotoxicity is at least equal to that of conventional CAR-T cells, while their intrinsic cytotoxic activity is maintained. Thus, CAR-NKT cells may represent a valuable alternative to conventional CAR-T cells for cancer immunotherapy. Full article

(This article belongs to the Special Issue Cancer Immunology and Immunotherapy)

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Review

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21 pages, 945 KiB

Open AccessReview

Mutant p53 as an Antigen in Cancer Immunotherapy

by Navid Sobhani, Alberto D’Angelo, Xu Wang, Ken H. Young, Daniele Generali and Yong Li

Int. J. Mol. Sci. 2020, 21(11), 4087; https://doi.org/10.3390/ijms21114087 - 8 Jun 2020

Cited by 17 | Viewed by 6738

Abstract

The p53 tumor suppressor plays a pivotal role in cancer and infectious disease. Many oncology treatments are now calling on immunotherapy approaches, and scores of studies have investigated the role of p53 antibodies in cancer diagnosis and therapy. This review summarizes the current knowledge from the preliminary evidence that suggests a potential role of p53 as an antigen in the adaptive immune response and as a key monitor of the innate immune system, thereby speculating on the idea that mutant p53 antigens serve as a druggable targets in immunotherapy. Except in a few cases, the vast majority of published work on p53 antibodies in cancer patients use wild-type p53 as the antigen to detect these antibodies and it is unclear whether they can recognize p53 mutants carried by cancer patients at all. We envision that an antibody targeting a specific mutant p53 will be effective therapeutically against a cancer carrying the exact same mutant p53. To corroborate such a possibility, a recent study showed that a T cell receptor-like (TCLR) antibody, initially made for a wild-type antigen, was capable of discriminating between mutant p53 and wild-type p53, specifically killing more cancer cells expressing mutant p53 than wild-type p53 in vitro and inhibiting the tumour growth of mice injected with mutant p53 cancer cells than mice with wild-type p53 cancer cells. Thus, novel antibodies targeting mutant p53, but not the wild-type isoform, should be pursued in preclinical and clinical studies. Full article

(This article belongs to the Special Issue Cancer Immunology and Immunotherapy)

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12 pages, 662 KiB

Open AccessReview

Contribution of Aging, Obesity, and Microbiota on Tumor Immunotherapy Efficacy and Toxicity

by Regina E. M. Baiden-Amissah and Sandra Tuyaerts

Int. J. Mol. Sci. 2019, 20(14), 3586; https://doi.org/10.3390/ijms20143586 - 23 Jul 2019

Cited by 19 | Viewed by 4407

Abstract

Cancer immunotherapy has entered the forefront of cancer treatment, but major challenges still exist, such as the limited proportion of patients that respond to treatment and treatment-related toxicity. Therefore, biomarkers to predict which patients will benefit from therapy without major side effects are of the utmost importance. Moreover, novel therapeutic targets to increase the proportion of responding patients on a given immunotherapy or to alleviate immunotherapy-induced toxicity could be a valuable adjunct to immunotherapy treatment. Host factors such as age, obesity, and the composition of the gut microbiome have considerable effects on immune responses and, hence, could have a large impact on the outcome of immunotherapies. Moreover, since these host factors differ considerably between preclinical mouse models and human cancer patients, it might be possible that these host factors account, in part, for the observed discrepancies in outcomes between mice experiments and clinical trials. In this review, we discuss the latest data on the influence of aging, obesity, and the gut microbiome on the anti-tumor immune response and immunotherapy and propose avenues to increase our knowledge on this topic in order to improve patient selection for cancer immunotherapy treatment. Full article

(This article belongs to the Special Issue Cancer Immunology and Immunotherapy)

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16 pages, 616 KiB

Open AccessReview

Ovarian Cancer Immunotherapy: Turning up the Heat

by Eleonora Ghisoni, Martina Imbimbo, Stefan Zimmermann and Giorgio Valabrega

Int. J. Mol. Sci. 2019, 20(12), 2927; https://doi.org/10.3390/ijms20122927 - 15 Jun 2019

Cited by 110 | Viewed by 10533

Abstract

Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological malignancies. Despite surgery and chemotherapy, 5-years survival rates have improved only modestly over the past few decades remaining at 45% for advanced stages. Therefore, novel therapies are urgently needed. The presence of tumor-infiltrating lymphocytes (TILs) in OC tumor microenvironment (TME) has already proved to be correlated with overall survival (OS), while immune evasion mechanisms are associated with poor prognosis. Although these data indicate that immunotherapy has a strong rationale in OC, single agent immune-checkpoints inhibitors (ICIs) have shown only modest results in this malignancy. In this review, we will discuss immune-targeting combination therapies and adoptive cell therapy (ACT), highlighting the challenges represented by these strategies, which aim at disrupting the stroma-tumor barrier to boost immune system against ovarian cancer. Full article

(This article belongs to the Special Issue Cancer Immunology and Immunotherapy)

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20 pages, 2967 KiB

Open AccessReview

Exosomes and the Future of Immunotherapy in Pancreatic Cancer

by Ines A. Batista and Sonia A. Melo

Int. J. Mol. Sci. 2019, 20(3), 567; https://doi.org/10.3390/ijms20030567 - 29 Jan 2019

Cited by 66 | Viewed by 8989

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease, associated with a late diagnosis and a five-year survival rate of 8%. Currently available treatments fall short in improving the survival and quality of life of PDAC patients. The only possible curative option is still the surgical resection of the tumor. Exosomes are extracellular vesicles secreted by cells that transport proteins, lipids, and nucleic acids to other cells, triggering phenotypic changes in the recipient cells. Tumor cells often secrete increased amounts of exosomes. Tumor exosomes are now accepted as important players in the remodeling of PDAC tumor stroma, particularly in the establishment of an immunosuppressive microenvironment. This has sparked the interest in their usefulness as mediators of immunomodulatory effects for the treatment of PDAC. In fact, exosomes are now under study to understand their potential as nanocarriers to stimulate an immune response against cancer. This review highlights the latest findings regarding the function of exosomes in tumor-driven immunomodulation, and the challenges and advantages associated with the use of these vesicles to potentiate immunotherapy in PDAC. Full article

(This article belongs to the Special Issue Cancer Immunology and Immunotherapy)

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