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Cancer-Mediated Immunomodulation—Pathogenetic, Diagnostic and Therapeutic Aspects

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (1 May 2021) | Viewed by 38165

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Special Issue Editor

Prof. Lucia Mincheva-Nilsson

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Guest Editor

Department of Clinical Microbiology/Clinical Immunology, Umeå University, S-90185, Umeå, Sweden.
Interests: ovarian cancer; tumor microenvironment; tumor immune escape; cancer exosomes; immunosuppression; cytokines; NK cells; cytotoxicity; NKG2D receptor; NKG2D ligands

Special Issue Information

Dear Colleagues,

Besides its primary involvement in the defense against pathogens, the immune system plays a pivotal role guarding the homeostasis and integrity of the organism and is now widely acknowledged as an essential factor with a decisive influence on the curability, prognosis, and outcome of cancer. The concept of cancer immunosurveillance was first proposed a century ago, but it was not until it was experimentally proved in the recent decades that oncoimmunology research, studying the complex interactions of tumor cells and the immune system, has achieved a great progress in understanding immunomodulation in cancer and has been instrumental in the development of novel diagnostic and immunotherapeutic strategies.

We wish to dedicate this Special Issue of Cancers to the intricate interplay between cancer and immunity, with a broad focus on all types of tumor and all its aspects, from the current understanding of cancer immunology in general and in particular cancer types—including immunosurveillance and immunoediting, tumor microenvironment, immune cells (T cells, B cells, natural killer cells, macrophages, dendritic cells, T regulatory cells, myelosuppressive cells), cancer and cancer stem cells, exosomes, cytokines, immune mechanisms, checkpoints, and regulators—to novel diagnostic tools and novel immune therapies able to reverse immune evasion and eliminate a tumor. The focus of this Special Issue is your current research and your current understanding of oncoimmunology. With your contribution of original articles and/or reviews, you will help us highlight the current state of the art in oncoimmunology and in your specific area of cancer research.

Prof. Lucia Mincheva-Nilsson
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

cancer microenvironment
immunoediting and immune escape
exosomes
cytokines
tumor markers
liquid biopsy
cancer immune therapy
checkpoint inhibition
adoptive transfer
CAR T cells

Published Papers (12 papers)

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Research

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15 pages, 28653 KiB

Open AccessArticle

Labile Heme and Heme Oxygenase-1 Maintain Tumor-Permissive Niche for Endometriosis-Associated Ovarian Cancer

by Jonathan L. Hecht, Monika Janikova, Reeham Choudhury, Fong Liu, Giacomo Canesin, Lubica Janovicova, Eva Csizmadia, Elisa M. Jorgensen, Katharine M. Esselen, Peter Celec, Kenneth D. Swanson and Barbara Wegiel

Cancers 2022, 14(9), 2242; https://doi.org/10.3390/cancers14092242 - 29 Apr 2022

Cited by 5 | Viewed by 2217

Abstract

Endometriosis, a painful gynecological condition accompanied by inflammation in women of reproductive age, is associated with an increased risk of ovarian cancer. We evaluated the role of peritoneal heme accumulated during menstrual cycling, as well as peritoneal and lesional macrophage phenotype, in promoting an oncogenic microenvironment. We quantified the heme-degrading enzyme, heme oxygenase-1 (HO-1, encoded by Hmox1) in normal peritoneum, endometriotic lesions and endometriosis-associated ovarian cancer (EAOC) of clear cell type (OCCC). HO-1 was expressed primarily in macrophages and increased in endometrioma and OCCC tissues relative to endometriosis and controls. Further, we compared cytokine expression profiles in peritoneal macrophages (PM) and peripheral blood mononuclear cells (PBMC) in women with endometriosis versus controls as a measure of a tumor-promoting environment in the peritoneum. We found elevated levels of HO-1 along with IL-10 and the pro-inflammatory cytokines (IL-1β, IL-16, IFNγ) in PM but not in PBMC from endometriosis patients. Using LysM-Cre:Hmox1^flfl conditional knockout mice, we show that a deficiency of HO-1 in macrophages led to the suppression of growth of ID8 ovarian tumors implanted into the peritoneum. The restriction of ID8 ovarian tumor growth was associated with an increased number of Mac3⁺ macrophage and B cells in LysM-Cre:Hmox1^flfl mice compared to controls. Functional experiments in ovarian cancer cell lines show that HO-1 is induced by heme. Low levels of exogenous heme promoted ovarian cancer colony growth in soft agar. Higher doses of heme led to slower cancer cell colony growth in soft agar and the induction of HO-1. These data suggest that perturbation of heme metabolism within the endometriotic niche and in cancer cells themselves may be an important factor that influences tumor initiation and growth. Full article

(This article belongs to the Special Issue Cancer-Mediated Immunomodulation—Pathogenetic, Diagnostic and Therapeutic Aspects)

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19 pages, 4646 KiB

Open AccessArticle

The Fatty Acid and Protein Profiles of Circulating CD81-Positive Small Extracellular Vesicles Are Associated with Disease Stage in Melanoma Patients

by Giovanni Paolino, Veronica Huber, Serena Camerini, Marialuisa Casella, Alberto Macone, Lucia Bertuccini, Francesca Iosi, Elisa Moliterni, Serena Cecchetti, Irene Ruspantini, Flavia Chiarotti, Elisabetta Vergani, Luca Lalli, Carla Raggi, Antonella Di Biase, Stefano Calvieri, Santo Raffaele Mercuri, Luana Lugini and Cristina Federici

Cancers 2021, 13(16), 4157; https://doi.org/10.3390/cancers13164157 - 18 Aug 2021

Cited by 18 | Viewed by 2776

Abstract

The early detection of cutaneous melanoma, a potentially lethal cancer with rising incidence, is fundamental to increasing survival and therapeutic adjustment. In stages II–IV especially, additional indications for adjuvant therapy purposes after resection and for treatment of metastatic patients are urgently needed. We investigated whether the fatty acid (FA) and protein compositions of small extracellular vesicles (sEV) derived from the plasma of stage 0–I, II and III–IV melanoma patients (n = 38) could reflect disease stage. The subpopulation of sEV expressing CD81 EV marker (CD81sEV) was captured by an ad hoc immune affinity technique from plasma depleted of large EV. Biological macromolecules were investigated by gas chromatography and mass spectrometry in CD81sEV. A higher content of FA was detectable in patients with respect to healthy donors (HD). Moreover, a higher C18:0/C18:1 ratio, as a marker of cell membrane fluidity, distinguished early (stage 0–I) from late (III–IV) stages’ CD81sEV. Proteomics detected increases in CD14, PON1, PON3 and APOA5 exclusively in stage II CD81sEV, and RAP1B was decreased in stage III–IV CD81sEV, in comparison to HD. Our results suggest that stage dependent alterations in CD81sEV’ FA and protein composition may occur early after disease onset, strengthening the potential of circulating sEV as a source of discriminatory information for early diagnosis, prediction of metastatic behavior and following up of melanoma patients. Full article

(This article belongs to the Special Issue Cancer-Mediated Immunomodulation—Pathogenetic, Diagnostic and Therapeutic Aspects)

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19 pages, 2334 KiB

Open AccessArticle

Proteomic Profiling of Tissue Exosomes Indicates Continuous Release of Malignant Exosomes in Urinary Bladder Cancer Patients, Even with Pathologically Undetectable Tumour

by Maria Eldh, Michael Mints, Stefanie Hiltbrunner, Sam Ladjevardi, Farhood Alamdari, Markus Johansson, Tomasz Jakubczyk, Rosanne E. Veerman, Ola Winqvist, Amir Sherif and Susanne Gabrielsson

Cancers 2021, 13(13), 3242; https://doi.org/10.3390/cancers13133242 - 29 Jun 2021

Cited by 12 | Viewed by 2685

Abstract

Invasive urothelial bladder cancer (UBC) has high recurrence rates even after radical cystectomy (RC). Exosomes are membrane-bound nanovesicles, which have been shown to contribute to carcinogenesis and metastasis. We previously showed that urinary exosomes display a malignant profile in UBC patients despite the absence of detectable tumour. Here, we investigated exosomes from sampling sites close to or distant from the former tumour, aiming to understand the effect of the tumour on the local milieu. Ten patients scheduled for cystectomy after transurethral bladder resection (TUR-B), without remaining detectable tumour, were included. Exosomes were isolated from tissue explants of both the previous tumour site and distant bladder tissue. Proteins were quantified by mass spectrometry in seven patients. Exosomes from the previous tumour site were enriched in inflammatory but not cancer-related pathways compared to distant tissue. However, the 69 most abundant proteins in tissue-derived exosomes regardless of site, 20 of which were also found in urinary exosomes from our previous study, were enriched for cancer-related metabolic pathways and associated with poor prognosis in an external mRNA dataset. The enrichment of cancer-related pathways in the most abundant proteins, regardless of sampling site, confirms our hypothesis that despite the absence of detectable tumour, the entire bladder releases exosomes that contribute to metastasis and highlights the need for early RC. Full article

(This article belongs to the Special Issue Cancer-Mediated Immunomodulation—Pathogenetic, Diagnostic and Therapeutic Aspects)

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14 pages, 1035 KiB

Open AccessArticle

High Monocyte Count and Expression of S100A9 and S100A12 in Peripheral Blood Mononuclear Cells Are Associated with Poor Outcome in Patients with Metastatic Prostate Cancer

by Anna-Maja Åberg, Sofia Halin Bergström, Elin Thysell, Lee-Ann Tjon-Kon-Fat, Jonas A. Nilsson, Anders Widmark, Camilla Thellenberg-Karlsson, Anders Bergh, Pernilla Wikström and Marie Lundholm

Cancers 2021, 13(10), 2424; https://doi.org/10.3390/cancers13102424 - 17 May 2021

Cited by 5 | Viewed by 2403

Abstract

Increasing evidence indicates calcium-binding S100 protein involvement in inflammation and tumor progression. In this prospective study, we evaluated the mRNA levels of two members of this family, S100A9 and S100A12, in peripheral blood mononuclear cells (PBMCs) in a cohort of 121 prostate cancer patients using RT-PCR. Furthermore, monocyte count was determined by flow cytometry. By stratifying patients into different risk groups, according to TNM stage, Gleason score and PSA concentration at diagnosis, expression of S100A9 and S100A12 was found to be significantly higher in patients with metastases compared to patients without clinically detectable metastases. In line with this, we observed that the protein levels of S100A9 and S100A12 in plasma were higher in patients with advanced disease. Importantly, in patients with metastases at diagnosis, high monocyte count and high levels of S100A9 and S100A12 were significantly associated with short progression free survival (PFS) after androgen deprivation therapy (ADT). High monocyte count and S100A9 levels were also associated with short cancer-specific survival, with monocyte count providing independent prognostic information. These findings indicate that circulating levels of monocytes, as well as S100A9 and S100A12, could be biomarkers for metastatic prostate cancer associated with particularly poor prognosis. Full article

(This article belongs to the Special Issue Cancer-Mediated Immunomodulation—Pathogenetic, Diagnostic and Therapeutic Aspects)

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17 pages, 6851 KiB

Open AccessArticle

Simultaneous Expression of Th1- and Treg-Associated Chemokine Genes and CD4⁺, CD8⁺, and Foxp3⁺ Cells in the Premalignant Lesions of 4NQO-Induced Mouse Tongue Tumorigenesis

by Hana Yamaguchi, Miki Hiroi, Kazumasa Mori, Ryosuke Ushio, Ari Matsumoto, Nobuharu Yamamoto, Jun Shimada and Yoshihiro Ohmori

Cancers 2021, 13(8), 1835; https://doi.org/10.3390/cancers13081835 - 12 Apr 2021

Cited by 9 | Viewed by 2704

Abstract

Chemokines and cytokines in the tumor microenvironment influence immune cell infiltration and activation. To elucidate their role in immune cell recruitment during oral cancer development, we generated a mouse tongue cancer model using the carcinogen 4-nitroquinoline 1-oxide (4NQO) and investigated the carcinogenetic process and chemokine/cytokine gene expression kinetics in the mouse tongue. C57/BL6 mice were administered 4NQO in drinking water, after which tongues were dissected at 16 and 28 weeks and subjected to analysis using the RT² Profiler PCR Array, qRT-PCR, and pathologic and immunohistochemical analyses. We found that Th1-associated chemokine/cytokine (Cxcl9, Cxcl10, Ccl5, and Ifng) and Treg-associated chemokine/cytokine (Ccl17, Ccl22, and Il10) mRNA levels were simultaneously increased in premalignant lesions of 4NQO-treated mice at 16 weeks. Additionally, although levels of Gata3, a Th2 marker, were not upregulated, those of Cxcr3, Ccr4, and Foxp3 were upregulated in the tongue tissue. Furthermore, immunohistochemical analysis confirmed the infiltration of CD4⁺, CD8⁺, and Foxp3⁺ cells in the tongue tissue of 4NQO-treated mice, as well as significant correlations between Th1- or Treg-associated chemokine/cytokine mRNA expression and T cell infiltration. These results indicate that CD4⁺, CD8⁺, and Foxp3⁺ cells were simultaneously recruited through the expression of Th1- and Treg-associated chemokines in premalignant lesions of 4NQO-induced mouse tongue tissue. Full article

(This article belongs to the Special Issue Cancer-Mediated Immunomodulation—Pathogenetic, Diagnostic and Therapeutic Aspects)

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9 pages, 1046 KiB

Open AccessCommunication

Value of the Lung Immune Prognostic Index in Patients with Non-Small Cell Lung Cancer Initiating First-Line Atezolizumab Combination Therapy: Subgroup Analysis of the IMPOWER150 Trial

by Ashley M. Hopkins, Ganessan Kichenadasse, Ahmad Y. Abuhelwa, Ross A. McKinnon, Andrew Rowland and Michael J. Sorich

Cancers 2021, 13(5), 1176; https://doi.org/10.3390/cancers13051176 - 09 Mar 2021

Cited by 18 | Viewed by 3661

Abstract

The lung immune prognostic index (LIPI) is proposed to differentiate prognosis and treatment benefit from immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (NSCLC). There is minimal information on the predictive importance with first-line, combination ICI approaches. In post-hoc analysis of IMpower150, Cox-proportional hazard analysis assessed the association between LIPI groups and overall survival (OS)/progression free survival (PFS). IMpower150 involved chemotherapy-naïve, metastatic non-squamous NSCLC participants randomized atezolizumab-carboplatin-paclitaxel (ACP), bevacizumab-carboplatin-paclitaxel (BCP), or atezolizumab-BCP (ABCP). Good (0 factors), intermediate (1 factor), and poor LIPI (2 factors) were defined via derived neutrophil-to-lymphocyte ratio >3, and lactate dehydrogenase >upper limit of normal. Of 1148 participants, 548 had good, 479 intermediate, and 121 poor LIPI. In 385 participants randomised ABCP, a significant association between LIPI and OS (HR (95%CI): intermediate LIPI = 2.16 (1.47–3.18), poor LIPI = 5.28 (3.20–8.69), p < 0.001) and PFS (HR (95%CI): intermediate LIPI = 1.47 (1.11–1.95), poor LIPI = 3.02 (2.03–4.50), p < 0.001) was identified. Median OS was 24, 16, and 7 months for good, intermediate, and poor LIPI, respectively. ACP associations were similar. Relative OS treatment effect (HR 95%CI) of ABCP vs. BCP was 0.78 (0.53–1.15), 0.67 (0.49–0.91), and 0.87 (0.51–1.47) for the good, intermediate, and poor LIPI groups, respectively (P(interaction) = 0.66), with no benefit in median OS observed in the poor LIPI group. LIPI identified subgroups with significantly different survival following ABCP and ACP initiation for chemotherapy-naïve, metastatic non-squamous NSCLC. There was insufficient evidence that LIPI identifies patients unlikely to benefit from ABCP treatment. Full article

(This article belongs to the Special Issue Cancer-Mediated Immunomodulation—Pathogenetic, Diagnostic and Therapeutic Aspects)

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22 pages, 3162 KiB

Open AccessArticle

Soluble and Exosome-Bound α-Galactosylceramide Mediate Preferential Proliferation of Educated NK Cells with Increased Anti-Tumor Capacity

by Arnika K. Wagner, Ulf Gehrmann, Stefanie Hiltbrunner, Valentina Carannante, Thuy T. Luu, Tanja I. Näslund, Hanna Brauner, Nadir Kadri, Klas Kärre and Susanne Gabrielsson

Cancers 2021, 13(2), 298; https://doi.org/10.3390/cancers13020298 - 15 Jan 2021

Cited by 3 | Viewed by 3393

Abstract

Natural killer (NK) cells can kill target cells via the recognition of stress molecules and down-regulation of major histocompatibility complex class I (MHC-I). Some NK cells are educated to recognize and kill cells that have lost their MHC-I expression, e.g., tumor or virus-infected cells. A desired property of cancer immunotherapy is, therefore, to activate educated NK cells during anti-tumor responses in vivo. We here analyze NK cell responses to α-galactosylceramide (αGC), a potent activator of invariant NKT (iNKT) cells, or to exosomes loaded with αGC. In mouse strains which express different MHC-I alleles using an extended NK cell flow cytometry panel, we show that αGC induces a biased NK cell proliferation of educated NK cells. Importantly, iNKT cell-induced activation of NK cells selectively increased in vivo missing self-responses, leading to more effective rejection of tumor cells. Exosomes from antigen-presenting cells are attractive anti-cancer therapy tools as they may induce both innate and adaptive immune responses, thereby addressing the hurdle of tumor heterogeneity. Adding αGC to antigen-loaded dendritic-cell-derived exosomes also led to an increase in missing self-responses in addition to boosted T and B cell responses. This study manifests αGC as an attractive adjuvant in cancer immunotherapy, as it increases the functional capacity of educated NK cells and enhances the innate, missing self-based antitumor response. Full article

(This article belongs to the Special Issue Cancer-Mediated Immunomodulation—Pathogenetic, Diagnostic and Therapeutic Aspects)

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Review

Jump to: Research, Other

16 pages, 1286 KiB

Open AccessReview

Serum Amyloid A Proteins and Their Impact on Metastasis and Immune Biology in Cancer

by Jesse Lee and Gregory L. Beatty

Cancers 2021, 13(13), 3179; https://doi.org/10.3390/cancers13133179 - 25 Jun 2021

Cited by 12 | Viewed by 3662

Abstract

Cancer triggers the systemic release of inflammatory molecules that support cancer cell metastasis and immune evasion. Notably, this biology shows striking similarity to an acute phase response that is coordinated by the liver. Consistent with this, a role for the liver in defining cancer biology is becoming increasingly appreciated. Understanding the mechanisms that link acute phase biology to metastasis and immune evasion in cancer may reveal vulnerable pathways and novel therapeutic targets. Herein, we discuss a link between acute phase biology and cancer with a focus on serum amyloid A proteins and their involvement in regulating the metastatic cascade and cancer immunobiology. Full article

(This article belongs to the Special Issue Cancer-Mediated Immunomodulation—Pathogenetic, Diagnostic and Therapeutic Aspects)

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22 pages, 1178 KiB

Open AccessReview

Interactions between Cancer-Associated Fibroblasts and T Cells in the Pancreatic Tumor Microenvironment and the Role of Chemokines

by Laia Gorchs and Helen Kaipe

Cancers 2021, 13(12), 2995; https://doi.org/10.3390/cancers13122995 - 15 Jun 2021

Cited by 28 | Viewed by 4333

Abstract

Less than 10% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) survive 5 years or more, making it one of the most fatal cancers. Accumulation of T cells in pancreatic tumors is associated with better prognosis, but immunotherapies to enhance the anti-tumor activity of infiltrating T cells are failing in this devastating disease. Pancreatic tumors are characterized by a desmoplastic stroma, which mainly consists of activated cancer-associated fibroblasts (CAFs). Pancreatic CAFs have emerged as important regulators of the tumor microenvironment by contributing to immune evasion through the release of chemokines, cytokines, and growth factors, which alters T-cell migration, differentiation and cytotoxic activity. However, recent discoveries have also revealed that subsets of CAFs with diverse functions can either restrain or promote tumor progression. Here, we discuss our current knowledge about the interactions between CAFs and T cells in PDAC and summarize different therapy strategies targeting the CAF–T cell axis with focus on CAF-derived soluble immunosuppressive factors and chemokines. Identifying the functions of different CAF subsets and understanding their roles in T-cell trafficking within the tumor may be fundamental for the development of an effective combinational treatment for PDAC. Full article

(This article belongs to the Special Issue Cancer-Mediated Immunomodulation—Pathogenetic, Diagnostic and Therapeutic Aspects)

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13 pages, 1524 KiB

Open AccessReview

Emerging Next-Generation Target for Cancer Immunotherapy Research: The Orphan Nuclear Receptor NR2F6

by Victoria Klepsch, Kerstin Siegmund and Gottfried Baier

Cancers 2021, 13(11), 2600; https://doi.org/10.3390/cancers13112600 - 26 May 2021

Cited by 10 | Viewed by 6394

Abstract

Additional therapeutic targets suitable for boosting anti-tumor effector responses have been found inside effector CD4⁺ and CD8⁺ T cells. It is likely that future treatment options will combine surface receptor and intracellular protein targets. Utilizing germline gene ablation as well as CRISPR/Cas9-mediated acute gene mutagenesis, the nuclear receptor NR2F6 (nuclear receptor subfamily 2 group F member 6, also called Ear-2) has been firmly characterized as such an intracellular immune checkpoint in effector T cells. Targeting this receptor appears to be a strategy for improving anti-tumor immunotherapy responses, especially in combination with CTLA-4 and PD-1. Current preclinical experimental knowledge firmly validates the immune checkpoint function of NR2F6 in murine tumor models, which provides a promising perspective for immunotherapy regimens in humans in the near future. While the clinical focus remains on the B7/CD28 family members, protein candidate targets such as NR2F6 are now being investigated in laboratories around the world and in R&D companies. Such an alternative therapeutic approach, if demonstrated to be successful, could supplement the existing therapeutic models and significantly increase response rates of cancer patients and/or expand the reach of immune therapy regimens to include a wider range of cancer entities. In this perspective review, the role of NR2F6 as an emerging and druggable target in immuno-oncology research will be discussed, with special emphasis on the unique potential of NR2F6 and its critical and non-redundant role in both immune and tumor cells. Full article

(This article belongs to the Special Issue Cancer-Mediated Immunomodulation—Pathogenetic, Diagnostic and Therapeutic Aspects)

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