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The role of DNA damage repair (DDR) system in response to immune checkpoint inhibitor (ICI) therapy.

ABSTRACT: As our understanding of the mechanisms of cancer treatment has increased, a growing number of studies demonstrate pathways through which DNA damage repair (DDR) affects the immune system. At the same time, the varied response of patients to immune checkpoint blockade (ICB) therapy has prompted the discovery of various predictive biomarkers and the study of combination therapy. Here, our investigation explores the interactions involved in combination therapy, accompanied by a review that summarizes currently identified and promising predictors of response to immune checkpoint inhibitors (ICIs) that are useful for classifying oncology patients. In addition, this work, which discusses immunogenicity and several components of the tumor immune microenvironment, serves to illustrate the mechanism by which higher response rates and improved efficacy of DDR inhibitors (DDRi) in combination with ICIs are achieved.

SUBMITTER: Shi C

PROVIDER: S-EPMC9450390 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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The role of DNA damage repair (DDR) system in response to immune checkpoint inhibitor (ICI) therapy.

Shi Congqi C Qin Kaiyu K Lin Anqi A Jiang Aimin A Cheng Quan Q Liu Zaoqu Z Zhang Jian J Luo Peng P

Journal of experimental & clinical cancer research : CR 20220907 1

As our understanding of the mechanisms of cancer treatment has increased, a growing number of studies demonstrate pathways through which DNA damage repair (DDR) affects the immune system. At the same time, the varied response of patients to immune checkpoint blockade (ICB) therapy has prompted the discovery of various predictive biomarkers and the study of combination therapy. Here, our investigation explores the interactions involved in combination therapy, accompanied by a review that summariz ...[more]

PMID: 36071479

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Project description:The Philadelphia chromosome-negative (Ph-) myeloproliferative neoplasms (MPNs), which include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are enduring and well-known conditions. These disorders are characterized by the abnormal growth of one or more hematopoietic cell lineages in the body's stem cells, leading to the enlargement of organs and the manifestation of constitutional symptoms. Numerous studies have provided evidence indicating that the pathogenesis of these diseases involves the dysregulation of the immune system and the presence of chronic inflammation, both of which are significant factors. Lately, the treatment of cancer including hematological malignancy has progressed on the agents aiming for the immune system, cytokine environment, immunotherapy agents, and targeted immune therapy. Immune checkpoints are the molecules that regulate T cell function in the tumor microenvironment (TME). The first line of primary immune checkpoints are programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte antigen-4 (CTLA-4). Immune checkpoint inhibitor therapy (ICIT) exerts its anti-tumor actions by blocking the inhibitory pathways in T cells and has reformed cancer treatment. Despite the impressive clinical success of ICIT, tumor internal resistance poses a challenge for oncologists leading to a low response rate in solid tumors and hematological malignancies. A Phase II trial on nivolumab for patients with post-essential thrombocythemia myelofibrosis, primary myelofibrosis, or post-polycythemia myelofibrosis was performed (Identifier: NCT02421354). This trial tested the efficacy of a PD-1 blockade agent, namely nivolumab, but was terminated prematurely due to adverse events and lack of efficacy. A multicenter, Phase II, single-arm open-label study was conducted including pembrolizumab in patients with primary thrombocythemia, post-essential thrombocythemia or post-polycythemia vera myelofibrosis that were ineligible for or were previously treated with ruxolitinib. This study showed that pembrolizumab treatment did not have many adverse events, but there were no pertinent clinical responses hence it was terminated after the first stage was completed. To avail the benefits from immunotherapy, the paradigm has shifted to new immune checkpoints in the TME such as lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin domain 3 (TIM-3), T cell immunoglobulin and ITIM domain (TIGIT), V-domain immunoglobulin-containing suppressor of T cell activation (VISTA), and human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) forming the basis of next-generation ICIT. The primary aim of this article is to underscore and elucidate the significance of next-generation ICIT in the context of MPN. Specifically, we aim to explore the potential of monoclonal antibodies as targeted immunotherapy and the development of vaccines targeting specific MPN epitopes, with the intent of augmenting tumor-related immune responses. It is anticipated that these therapeutic modalities rooted in immunotherapy will not only expand but also enhance the existing treatment regimens for patients afflicted with MPN. Preliminary studies from our laboratory showed over-expressed MDSC and over-expressed VISTA in MDSC, and in progenitor and immune cells directing the need for more clinical trials using next-generation ICI in the treatment of MPN.

Project description:BackgroundCancer diagnoses and deaths among the elderly (65 +) are expected to increase significantly over the next decade. Immune checkpoint inhibitors specifically target ICI genes and enhance immune system function. However, poor outcomes may be associated with aging.MethodsWe downloaded the Genomic Data Commons from the Cancer Genome Atlas (TCGA) and collected gene expression data from malignant melanoma (MM) tissues, the third level as the primary site. The CKTTD ICI genes database were applied and validated using the GEO database and lab experiments.ResultsIn 414 patients, 13 ICI genes were obtained as risk gene signature by univariate and multivariate Cox hazard models and were associated with poor survival in the older group. At 1, 3, and 5 years (79%, 76%, and 76%, respectively), we investigate TNFRFS4 gene and age prediction using novel nomogram-associated aging (HR = 1.79, P 0.001, CI = 1.32-2.45) with higher sensitivity testing.TNFRSF4 gene expression was significantly high in younger (15 years interval) MM patients (P < 0.001). By correlation analysis, a significant negative association was determined (P < 0.001). The validation of gene correlation from GEO (GSE59455) and (GSE22153) was obtained as external validation. We tested the TNFRSF4 protein levels by IHC in 14 melanoma tissue samples. TNFRSF4 expression was observed to be lower expressed in the older of melanoma tissues, and higher in the younger age group (P = 0.02). Besides the connectivity of ICI gene proteins, the biological processes of cell aging, aging, and the immune system were found to be highly related.ConclusionsAlong with the risk score evaluation, the ICI gene (TNFRSF4) was identified as a tumor suppressor gene related to inequalities in age survival and associated with immune cell infiltrations. The aging responses of melanoma patients and related gene expression need further investigation in order to identify potential therapeutic targets.

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The role of DNA damage repair (DDR) system in response to immune checkpoint inhibitor (ICI) therapy.

Publications

The role of DNA damage repair (DDR) system in response to immune checkpoint inhibitor (ICI) therapy.

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