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Special Issue "Novel Advances in Cancer Immunology: From Molecular Mechanisms to Therapeutic Applications"

Special Issue Editors
Special Issue Information
Keywords
Published Papers

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 5246

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Special Issue Editors

Prof. Dr. Yona Keisari

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Guest Editor

Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, P.O. Box 39040, Tel Aviv 6997801, Israel
Interests: cancer immunology; tumor ablation and in situ immunostimulation; alpha-particle-based radiotherapy
Special Issues, Collections and Topics in MDPI journals

Dr. Fabrizio Mattei

E-Mail Website
Guest Editor

Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00166 Rome, Italy
Interests: IL-33 pathway in cancer; eosinophils in tumor microenvironment; type I interferon pathways in cancer; tumor mouse models; organs-on-chip systems
Special Issues, Collections and Topics in MDPI journals

Dr. Anahid Jewett

E-Mail Website
Guest Editor

1. The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Division of Oral Biology and Medicine, School of Dentistry, University of California Los Angeles, Los Angeles, CA 90095, USA
2. The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, Los Angeles, CA 90095, USA
Interests: NK cells; tumor immunology; cancer immunotherapy
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Luyuan Li
E-Mail Website
Guest Editor

State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, The Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China
Interests: nanocarrier

Special Issue Information

Dear Colleagues,

Immune cells are important components of the tumor microenvironment, where they play a prominent role in favoring or contrasting cancer progression through direct and indirect activities. Cancer immunology is a growing field in charge of investigating the complex mechanisms and interactions between immune and cancer cells, with the aim of identifying therapeutic targets for immunotherapy-based approaches, as well as their possible combination with other anticancer treatment modalities. A previous Special Issue, entitled “Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities”, was very successful, and comprises 29 papers and reviews concerning various aspects of cancer immunology. However, cancer immunology is a vast and dynamic field, making it difficult to cover in one Special Issue. Therefore, we aim to work towards creating an additional Special Issue on this topic.

This Special Issue of Cells aims to present research articles and reviews expanding the scope of tumor immunology and its applications. Articles should focus on cellular and molecular mechanisms, whether immunological, tumor-cell-related or tumor-microenvironment-derived, involved in cancer elimination or progression. This Special Issue also aims to provide data from clinical and translational research on how such mechanisms may be translated to immunotherapy and combined therapeutic approaches. All scientists working in these fields are cordially invited to submit their manuscripts.

All papers will be published on an ongoing basis with full open access. We look forward to receiving your interesting contributions.

Prof. Dr. Yona Keisari
Dr. Fabrizio Mattei
Dr. Anahid Jewett
Prof. Dr. Luyuan Li
Guest Editors

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. Cells 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 2700 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

antitumor immunity
advanced in vitro cancer models
advanced in vivo models for translational research
cancer genomics
cancer metastasis
cancer stem cells and stemness in cancer
cell-based strategies: CART and CAR-NK
chemokines and chemokine receptors
chemotherapy
combination therapies
cytokines and cytokine receptors
drug repurposing
epigenetic modifications and immunotherapy
exosomes and cancer
molecular pathways in cancer
immunosuppression
immune cells in cancer
immune checkpoint inhibitors
immunotherapy
inflammation and cancer
immunodeficiencies and cancer
immunomodulation and targeted therapies
intratumor heterogeneity
mechanisms of carcinogenesis
novel biomarkers
microbiomes and immunotherapy
oncogenes
tumor suppressor genes
oncolytic viruses
radiotherapy
small-molecule immunomodulators
translational and clinical research
resistance to conventional therapies
therapeutic targets in cancer
tumor microenvironment
tumor animal models
tumor vaccines

Published Papers (6 papers)

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Research

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Open AccessArticle

The Cell-Autonomous Pro-Metastatic Activities of PD-L1 in Breast Cancer Are Regulated by N-Linked Glycosylation-Dependent Activation of STAT3 and STAT1

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Cells 2023, 12(19), 2338; https://doi.org/10.3390/cells12192338 (registering DOI) - 23 Sep 2023

Viewed by 162

Abstract

PD-L1 has been characterized as an inhibitory immune checkpoint, leading to the suppression of potential anti-tumor immune activities in many cancer types. In view of the relatively limited efficacy of immune checkpoint blockades against PD-L1 in breast cancer, our recent study addressed the possibility that in addition to its immune-inhibitory functions, PD-L1 promotes the pro-metastatic potential of the cancer cells themselves. Indeed, our published findings demonstrated that PD-L1 promoted pro-metastatic functions of breast cancer cells in a cell-autonomous manner, both in vitro and in vivo. These functions fully depended on the integrity of the S283 intracellular residue of PD-L1. Here, using siRNAs and the S283A-PD-L1 variant, we demonstrate that the cell-autonomous pro-metastatic functions of PD-L1—tumor cell proliferation and invasion, and release of the pro-metastatic chemokine CXCL8—required the activation of STAT3 and STAT1 in luminal A and triple-negative breast cancer cells. The cell-autonomous pro-metastatic functions of PD-L1 were potently impaired upon inhibition of N-linked glycosylation (kifunensine). Site-specific mutants at each of the N-linked glycosylation sites of PD-L1 (N35, N192, N200, and N219) revealed that they were all required for PD-L1-induced pro-metastatic functions to occur; the N219 site was the main regulator of STAT3 and STAT1 activation, with accompanying roles for N192 and N200 (depending on the cell type). Using a T cell-independent mouse system, we found that cells expressing N35A-PD-L1 and N219A-PD-L1 had a significantly lower tumorigenic and metastatic potential than cells expressing WT-PD-L1. TCGA analyses revealed significant associations between reduced survival and high levels of α-mannosidase II (inferring on N-linked glycosylation) in breast cancer patients. These findings suggest that N-linked glycosylation of PD-L1 may be used to screen for patients who are at greater risk of disease progression, and that modalities targeting N-linked glycosylated PD-L1 may lead to the inhibition of its cell-autonomous pro-metastatic functions and to lower tumor progression in breast cancer. Full article

(This article belongs to the Special Issue Novel Advances in Cancer Immunology: From Molecular Mechanisms to Therapeutic Applications)

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Open AccessArticle

Immunotherapy around the Clock: Impact of Infusion Timing on Stage IV Melanoma Outcomes

Lisa Gonçalves

Duarte Gonçalves

Teresa Esteban-Casanelles

Tiago Barroso

Inês Soares de Pinho

Raquel Lopes-Brás

Miguel Esperança-Martins

Vanessa Patel

Sofia Torres

Rita Teixeira de Sousa

André Mansinho

and

Luís Costa

Cells 2023, 12(16), 2068; https://doi.org/10.3390/cells12162068 - 15 Aug 2023

Viewed by 537

Abstract

Although the impact of circadian timing on immunotherapy has yet to be integrated into clinical practice, chronoimmunotherapy is an emerging and promising field as circadian oscillations are observed in immune cell numbers as well as the expression of immunotherapy targets, e.g., programmed cell death protein-1 and its ligand programmed death ligand 1. Concurrent retrospective studies suggest that morning infusions may lead to higher effectiveness of immune checkpoint inhibitors in melanoma, non-small cell lung cancer, and kidney cancer. This paper discusses the results of a retrospective study (2016–2022) exploring the impact of infusion timing on the outcomes of all 73 patients with stage IV melanoma receiving immunotherapy at a particular medical center. While the median overall survival (OS) was 24.2 months (95% confidence interval [CI] 9.04–39.8), for a median follow-up of 15.3 months, our results show that having more than 75% of infusions in the afternoon results in shorter median OS (14.9 vs. 38.1 months; hazard ratio 0.45 [CI 0.23–0.86]; p < 0.01) with more expressive impacts on particular subgroups: women, older patients, and patients with a lower tumor burden at the outset of immunotherapy. Our findings highlight the potential benefits of follow-up validation in prospective and translational randomized studies. Full article

(This article belongs to the Special Issue Novel Advances in Cancer Immunology: From Molecular Mechanisms to Therapeutic Applications)

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Open AccessArticle

Fundamental Characterization of Antibody Fusion-Single-Chain TNF Recombinant Proteins Directed against Costimulatory TNF Receptors Expressed by T-Lymphocytes

Mari Hikosaka Kuniishi

Naoto Ishii

and

Takanori So

Cells 2023, 12(12), 1596; https://doi.org/10.3390/cells12121596 - 09 Jun 2023

Viewed by 864

Abstract

The costimulatory signal regulated by the members of the tumor necrosis factor receptor (TNFR) superfamily expressed by T cells plays essential roles for T cell responses and has emerged as a promising target for cancer immunotherapy. However, it is unclear how the difference in TNFR costimulation contributes to T cell responses. In this study, to clarify the functional significance of four different TNFRs, OX40, 4-1BB, CD27 and GITR, we prepared corresponding single-chain TNF ligand proteins (scTNFLs) connected to IgG Fc domain with beneficial characteristics, i.e., Fc−scOX40L, Fc−sc4-1BBL, Fc−scCD27L (CD70) and Fc−scGITRL. Without intentional cross-linking, these soluble Fc−scTNFL proteins bound to corresponding TNFRs induced NF-kB signaling and promoted proliferative and cytokine responses in CD4⁺ and CD8⁺ T cells with different dose-dependencies in vitro. Mice injected with one of the Fc−scTNFL proteins displayed significantly augmented delayed-type hypersensitivity responses, showing in vivo activity. The results demonstrate that each individual Fc−scTNFL protein provides a critical costimulatory signal and exhibits quantitatively distinct activity toward T cells. Our findings provide important insights into the TNFR costimulation that would be valuable for investigators conducting basic research in cancer immunology and also have implications for T cell-mediated immune regulation by designer TNFL proteins. Full article

(This article belongs to the Special Issue Novel Advances in Cancer Immunology: From Molecular Mechanisms to Therapeutic Applications)

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Open AccessArticle

The Vicious Cycle of Melanoma-Microglia Crosstalk: Inter-Melanoma Variations in the Brain-Metastasis-Promoting IL-6/JAK/STAT3 Signaling Pathway

Maharrish Chelladurai

Suyeon Ryu

Romela I. Ramos

Metsada Pasmanik-Chor

Dave S. B. Hoon

and

Isaac P. Witz

Cells 2023, 12(11), 1513; https://doi.org/10.3390/cells12111513 - 30 May 2023

Cited by 1 | Viewed by 974

Abstract

Previous studies from our lab demonstrated that the crosstalk between brain-metastasizing melanoma cells and microglia, the macrophage-like cells of the central nervous system, fuels progression to metastasis. In the present study, an in-depth investigation of melanoma-microglia interactions elucidated a pro-metastatic molecular mechanism that drives a vicious melanoma-brain-metastasis cycle. We employed RNA-Sequencing, HTG miRNA whole transcriptome assay, and reverse phase protein arrays (RPPA) to analyze the impact of melanoma-microglia interactions on sustainability and progression of four different human brain-metastasizing melanoma cell lines. Microglia cells exposed to melanoma-derived IL-6 exhibited upregulated levels of STAT3 phosphorylation and SOCS3 expression, which, in turn, promoted melanoma cell viability and metastatic potential. IL-6/STAT3 pathway inhibitors diminished the pro-metastatic functions of microglia and reduced melanoma progression. SOCS3 overexpression in microglia cells evoked microglial support in melanoma brain metastasis by increasing melanoma cell migration and proliferation. Different melanomas exhibited heterogeneity in their microglia-activating capacity as well as in their response to microglia-derived signals. In spite of this reality and based on the results of the present study, we concluded that the activation of the IL-6/STAT3/SOCS3 pathway in microglia is a major mechanism by which reciprocal melanoma-microglia signaling engineers the interacting microglia to reinforce the progression of melanoma brain metastasis. This mechanism may operate differently in different melanomas. Full article

(This article belongs to the Special Issue Novel Advances in Cancer Immunology: From Molecular Mechanisms to Therapeutic Applications)

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Review

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Open AccessReview

Insight into Cancer Immunity: MHCs, Immune Cells and Commensal Microbiota

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Cells 2023, 12(14), 1882; https://doi.org/10.3390/cells12141882 - 18 Jul 2023

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Abstract

Cancer cells circumvent immune surveillance via diverse strategies. In accordance, a large number of complex studies of the immune system focusing on tumor cell recognition have revealed new insights and strategies developed, largely through major histocompatibility complexes (MHCs). As one of them, tumor-specific MHC-II expression (tsMHC-II) can facilitate immune surveillance to detect tumor antigens, and thereby has been used in immunotherapy, including superior cancer prognosis, clinical sensitivity to immune checkpoint inhibition (ICI) therapy and tumor-bearing rejection in mice. NK cells play a unique role in enhancing innate immune responses, accounting for part of the response including immunosurveillance and immunoregulation. NK cells are also capable of initiating the response of the adaptive immune system to cancer immunotherapy independent of cytotoxic T cells, clearly demonstrating a link between NK cell function and the efficacy of cancer immunotherapies. Eosinophils were shown to feature pleiotropic activities against a variety of solid tumor types, including direct interactions with tumor cells, and accessorily affect immunotherapeutic response through intricating cross-talk with lymphocytes. Additionally, microbial sequencing and reconstitution revealed that commensal microbiota might be involved in the modulation of cancer progression, including positive and negative regulatory bacteria. They may play functional roles in not only mucosal modulation, but also systemic immune responses. Here, we present a panorama of the cancer immune network mediated by MHCI/II molecules, immune cells and commensal microbiota and a discussion of prospective relevant intervening mechanisms involved in cancer immunotherapies. Full article

(This article belongs to the Special Issue Novel Advances in Cancer Immunology: From Molecular Mechanisms to Therapeutic Applications)

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Open AccessReview

Recent Emerging Immunological Treatments for Primary Brain Tumors: Focus on Chemokine-Targeting Immunotherapies

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Cells 2023, 12(6), 841; https://doi.org/10.3390/cells12060841 - 08 Mar 2023

Cited by 1 | Viewed by 1194

Abstract

Primary brain tumors are a leading cause of death worldwide and are characterized by extraordinary heterogeneity and high invasiveness. Current drug and radiotherapy therapies combined with surgical approaches tend to increase the five-year survival of affected patients, however, the overall mortality rate remains high, thus constituting a clinical challenge for which the discovery of new therapeutic strategies is needed. In this field, novel immunotherapy approaches, aimed at overcoming the complex immunosuppressive microenvironment, could represent a new method of treatment for central nervous system (CNS) tumors. Chemokines especially are a well-defined group of proteins that were so named due to their chemotactic properties of binding their receptors. Chemokines regulate the recruitment and/or tissue retention of immune cells as well as the mobilization of tumor cells that have undergone epithelial–mesenchymal transition, promoting tumor growth. On this basis, this review focuses on the function and involvement of chemokines and their receptors in primary brain tumors, specifically examining chemokine-targeting immunotherapies as one of the most promising strategies in neuro-oncology. Full article

(This article belongs to the Special Issue Novel Advances in Cancer Immunology: From Molecular Mechanisms to Therapeutic Applications)

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