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Molecular Drivers of Responsiveness to Cancer Immunotherapy

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 11861

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Special Issue Editors

Dr. Venkatesh Hegde

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Guest Editor

Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
Interests: mechanisms of immunosuppression; cannabinoid receptors; tumor immunology; anti-cancer vaccines; immunotherapeutics; immunosuppressive myeloid cells (MDSC)

Dr. Stephanie M. Dorta-Estremera

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Guest Editor

Cancer Biology Division, University of Puerto Rico Comprehensive Cancer Center, San Juan PR;Department of Microbiology and Medical Zoology, University of Puerto Rico Medical Sciences Campus, San Juan PR, Puerto Rico
Interests: tumor immunology; immunotherapy resistance; immune monitoring

Special Issue Information

Dear Colleagues,

Cancer immunotherapeutics such as cancer vaccines and immune checkpoint inhibitors act by activating the immune system against cancer. Despite recent advances and encouraging successes, the pressing problem is the resistance to these treatments in the majority of patients; for example, only <10–15% of patients respond to checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4. Therefore, understanding the mechanisms of resistance to immunotherapy as well as developing treatments to overcome resistance and improve responsiveness are critical areas of research. This Special Issue of the International Journal of Molecular Sciences will discuss emerging concepts in these areas. The topics will encompass molecular and cellular mechanisms of resistance to checkpoint blockade and anti-tumor vaccines, innate and acquired resistance, pathways of immunosuppression including suppressor cell populations, and approaches combining chemo-radiation or other targeted treatments to improve immunotherapy responsiveness and overall efficacy.

Dr. Venkatesh Hegde
Dr. Stephanie M. Dorta-Estremera
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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 vaccines
checkpoint blockade
cytokines and chemokines
immunosuppression
immunotherapy resistance
suppressor cells

Published Papers (4 papers)

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Research

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26 pages, 11013 KiB

Open AccessArticle

Comprehensive Analysis of FASN in Tumor Immune Infiltration and Prognostic Value for Immunotherapy and Promoter DNA Methylation

by Mingyang Zhang, Lei Yu, Yannan Sun, Li Hao, Jing Bai, Xinyu Yuan, Rihan Wu, Mei Hong, Pengxia Liu, Xiaojun Duan and Changshan Wang

Int. J. Mol. Sci. 2022, 23(24), 15603; https://doi.org/10.3390/ijms232415603 - 9 Dec 2022

Cited by 6 | Viewed by 1845

Abstract

Fatty acid synthase (FASN) promotes tumor progression in multiple cancers. In this study, we comprehensively examined the expression, prognostic significance, and promoter methylation of FASN, and its correlation with immune cell infiltration in pan-cancer. Our results demonstrated that elevated FASN expression was significantly associated with an unfavorable prognosis in many cancer types. Furthermore, FASN promoter DNA methylation can be used as a tumor prognosis marker. Importantly, high levels of FASN were significantly negatively correlated with tumor immune infiltration in 35 different cancers. Additionally, FASN was significantly associated with tumor mutational burden (TMB) and microsatellite instability (MSI) in multiple malignancies, suggesting that it may be essential for tumor immunity. We also investigated the effects of FASN expression on immunotherapy efficacy and prognosis. In up to 15 tumors, it was significantly negatively correlated with immunotherapy-related genes, such as PD-1, PD-L1, and CTLA-4. Moreover, we found that tumors with high FASN expression may be more sensitive to immunotherapy and have a good prognosis with PD-L1 treatment. Finally, we confirmed the tumor-suppressive effect of mir-195-5p through FASN. Altogether, our results suggested that FASN may serve as a novel prognostic indicator and immunotherapeutic target in various malignancies. Full article

(This article belongs to the Special Issue Molecular Drivers of Responsiveness to Cancer Immunotherapy)

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18 pages, 39949 KiB

Open AccessArticle

PODNL1 Methylation Serves as a Prognostic Biomarker and Associates with Immune Cell Infiltration and Immune Checkpoint Blockade Response in Lower-Grade Glioma

by Humaira Noor, Ashraf Zaman, Charles Teo and Michael E. Sughrue

Int. J. Mol. Sci. 2021, 22(22), 12572; https://doi.org/10.3390/ijms222212572 - 22 Nov 2021

Cited by 9 | Viewed by 2391

Abstract

Lower-grade glioma (LGG) is a diffuse infiltrative tumor of the central nervous system, which lacks targeted therapy. We investigated the role of Podocan-like 1 (PODNL1) methylation in LGG clinical outcomes using the TCGA-LGG transcriptomics dataset. We identified four PODNL1 CpG sites, cg07425555, cg26969888, cg18547299, and cg24354933, which were associated with unfavorable overall survival (OS) and disease-free survival (DFS) in univariate and multivariate analysis after adjusting for age, gender, tumor-grade, and IDH1-mutation. In multivariate analysis, the OS and DFS hazard ratios ranged from 0.44 to 0.58 (p < 0.001) and 0.62 to 0.72 (p < 0.001), respectively, for the four PODNL1 CpGs. Enrichment analysis of differential gene and protein expression and analysis of 24 infiltrating immune cell types showed significantly increased infiltration in LGGs and its histological subtypes with low-methylation levels of the PODNL1 CpGs. High PODNL1 expression and low-methylation subgroups of the PODNL1 CpG sites were associated with significantly increased PD-L1, PD-1, and CTLA4 expressions. PODNL1 methylation may thus be a potential indicator of immune checkpoint blockade response, and serve as a biomarker for determining prognosis and immune subtypes in LGG. Full article

(This article belongs to the Special Issue Molecular Drivers of Responsiveness to Cancer Immunotherapy)

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20 pages, 1394 KiB

Open AccessArticle

Molecular Mechanisms of PD-1 and PD-L1 Activity on a Pan-Cancer Basis: A Bioinformatic Exploratory Study

by Siddarth Kannan, Geraldine Martina O’Connor and Emyr Yosef Bakker

Int. J. Mol. Sci. 2021, 22(11), 5478; https://doi.org/10.3390/ijms22115478 - 22 May 2021

Cited by 7 | Viewed by 4214

Abstract

Immune checkpoint blockade targeting PD-1 (PDCD1)/PD-L1 (CD274) is increasingly used for multiple cancers. However, efficacy and adverse-related events vary significantly. This bioinformatic study interrogated molecular differences pertaining to PDCD1/CD274 and their correlated genes on a pan-cancer basis to identify differences between cancer types. Patient RNA-seq data from fifteen cancer types were accessed on cBioPortal to determine the role of PDCD1/CD274 in patient survival and to identify positively and negatively correlated genes, which were also assessed for clinical relevance. Genes correlating with PDCD1/CD274 across multiple cancers were taken forward for drug repurposing via DRUGSURV and microRNA analysis using miRDB and miRabel. MicroRNAs were also screened for clinical relevance using OncomiR. Forty genes were consistently correlated with PDCD1/CD274 across multiple cancers, with the cancers themselves exhibiting a differential role for the correlated genes in terms of patient survival. Esophageal and renal cancers in particular stood out in this regard as having a unique survival profile. Forty-nine putative microRNAs were identified as being linked to the PDCD1/CD274 network, which were taken forward and further assessed for clinical relevance using OncomiR and previously published literature. One hundred and thirty significant survival associations for 46 microRNAs across fourteen groups of cancers were identified. Finally, a total of 23 putative repurposed drugs targeting multiple components of the PDCD1/CD274 network were identified, which may represent immunotherapeutic adjuvants. Taken together, these results shed light on the varying PDCD1/CD274 networks between individual cancers and signpost a need for more cancer-specific investigations and treatments. Full article

(This article belongs to the Special Issue Molecular Drivers of Responsiveness to Cancer Immunotherapy)

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Review

Jump to: Research

22 pages, 999 KiB

Open AccessReview

Decoding Strategies to Evade Immunoregulators Galectin-1, -3, and -9 and Their Ligands as Novel Therapeutics in Cancer Immunotherapy

by Lee Seng Lau, Norhan B. B. Mohammed and Charles J. Dimitroff

Int. J. Mol. Sci. 2022, 23(24), 15554; https://doi.org/10.3390/ijms232415554 - 8 Dec 2022

Cited by 7 | Viewed by 2626

Abstract

Galectins are a family of ß-galactoside-binding proteins that play a variety of roles in normal physiology. In cancer, their expression levels are typically elevated and often associated with poor prognosis. They are known to fuel a variety of cancer progression pathways through their glycan-binding interactions with cancer, stromal, and immune cell surfaces. Of the 15 galectins in mammals, galectin (Gal)-1, -3, and -9 are particularly notable for their critical roles in tumor immune escape. While these galectins play integral roles in promoting cancer progression, they are also instrumental in regulating the survival, differentiation, and function of anti-tumor T cells that compromise anti-tumor immunity and weaken novel immunotherapies. To this end, there has been a surge in the development of new strategies to inhibit their pro-malignancy characteristics, particularly in reversing tumor immunosuppression through galectin–glycan ligand-targeting methods. This review examines some new approaches to evading Gal-1, -3, and -9–ligand interactions to interfere with their tumor-promoting and immunoregulating activities. Whether using neutralizing antibodies, synthetic peptides, glyco-metabolic modifiers, competitive inhibitors, vaccines, gene editing, exo-glycan modification, or chimeric antigen receptor (CAR)-T cells, these methods offer new hope of synergizing their inhibitory effects with current immunotherapeutic methods and yielding highly effective, durable responses. Full article

(This article belongs to the Special Issue Molecular Drivers of Responsiveness to Cancer Immunotherapy)

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