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Activation of DNA Damage Tolerance Pathways May Improve Immunotherapy of Mesothelioma.

ABSTRACT: Immunotherapy based on two checkpoint inhibitors (ICI), programmed cell death 1 (PD-1, Nivolumab) and cytotoxic T-lymphocyte 4 (CTLA-4, Ipilimumab), has provided a significant improvement in overall survival for malignant mesothelioma (MM). Despite this major breakthrough, the median overall survival of patients treated with the two ICIs only reached 18.1 months vs. 14 months in standard chemotherapy. With an objective response rate of 40%, only a subset of patients benefits from immunotherapy. A critical step in the success of immunotherapy is the presentation of tumor-derived peptides by the major histocompatibility complex I (MHC-I) of tumor cells. These neoantigens are potentially immunogenic and trigger immune responses orchestrated by cytotoxic cells. In MM, tumor development is nevertheless characterized by a low mutation rate despite major structural chromosomal rearrangements driving oncogenesis (BAP1, NF2, CDKN2AB). In this opinion, we propose to investigate an approach based on the mechanisms of the DNA damage tolerance (DDT) pathways to increase the frequency of non-synonymous mutations. The idea is to transiently activate the error-prone DDT in order to generate neoantigens while preserving a fully competent antitumor immune response.

SUBMITTER: Brossel H

PROVIDER: S-EPMC8269013 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Activation of DNA Damage Tolerance Pathways May Improve Immunotherapy of Mesothelioma.

Brossel Hélène H Fontaine Alexis A Hoyos Clotilde C Jamakhani Majeed M Willems Mégane M Hamaidia Malik M Willems Luc L

Cancers 20210627 13

Immunotherapy based on two checkpoint inhibitors (ICI), programmed cell death 1 (PD-1, Nivolumab) and cytotoxic T-lymphocyte 4 (CTLA-4, Ipilimumab), has provided a significant improvement in overall survival for malignant mesothelioma (MM). Despite this major breakthrough, the median overall survival of patients treated with the two ICIs only reached 18.1 months vs. 14 months in standard chemotherapy. With an objective response rate of 40%, only a subset of patients benefits from immunotherapy. ...[more]

PMID: 34199066

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Project description:Background Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. Although immunotherapy provides hope for advanced HCC patients, the outcomes are not satisfactory and vary by individual case. In this study, we sought to establish novel molecular subtypes and a stable model based on tumor-related pathways for guiding the immunotherapy in HCC patients. Methods A total of 15 pathways including immune pathways, stromal pathways, oncogenic pathways, and DNA damage repair pathways were used to construct molecular subtypes through consensus clustering. Immune characteristics, gene mutations, and genomic alterations including copy number variations and homologous recombination deficiency (HRD) were analyzed in different clusters. The Tumor Immune Dysfunction and Exclusion (TIDE) framework was used to predict the response to immunotherapy. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression were employed to screen prognostic genes for constructing a risk model. Results Three clusters/subtypes were constructed including Immune-E, Immune-D and Stromal-E. Immune-D had the worst prognosis and high enrichment of HRD pathways. Immune-E had higher immune infiltration, higher expression of major histocompatibility complex (MHC)-related genes, and higher expression of PD1, PDL1, CTLA4, and LAG3. TP53 alterations frequently occurred in Immune-D. Immune-E had a relatively high response to immunotherapy and was sensitive to chemotherapeutic drugs. Moreover, we constructed an IMScore model that was effective to classify HCC patients into different risk groups, and the IMScore had a better performance than the TIDE score. Conclusions This study revealed the complex interaction among the tumor microenvironment (TME), genomic alterations, and tumor-related pathways by exploring the molecular difference of 3 subtypes. The IMScore model has potential to provide guidance for immunotherapy in HCC patients.

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Activation of DNA Damage Tolerance Pathways May Improve Immunotherapy of Mesothelioma.

Publications

Activation of DNA Damage Tolerance Pathways May Improve Immunotherapy of Mesothelioma.

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