Abstract
Simple SummaryA 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 malignant mesothelioma (MM), tumor development is nevertheless characterized by a low mutation rate despite major structural chromosomal rearrangements driving oncogenesis. In this paper, we propose a paradigm 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.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.
Highlights
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The interaction between aquated cisplatin and GSH occurs non-enzymatically via a conjugation reaction or can be catalyzed by GSH-S-transferase (GSTp). Another cisplatin-resistance mechanism is associated with an increased capacity to correct the DNA lesions via the transcription-coupled nucleotide excision repair (TC-NER)
MM tumors are characterized by a low mutation rate despite major structural chromosomal rearrangements driving oncogenesis
Summary
Malignant mesothelioma (MM), a poor-prognosis cancer closely associated with asbestos exposure, affects mesothelial cells from the pleura, pericardium, and peritoneum [1]. ROS/RNS affect phosphodiester bonds of the DNA backbone, possibly leading to error-prone repair by non-homologous end joining (NHEJ) [3]. This mechanism may explain the presence of deletions and insertions in MM tumors (Figure 1A). Major genomic alterations affect a series of tumor-suppressor genes in human MM, e.g., the BRCA1-associated deubiquitylase (BAP1), the cyclin-dependent kinase inhibitor 2A/B (CDKN2AB), neurofibromatosis type. Major alterations in BAP1, CDKN2AB, and NF2 are predicted to drive oncogenesis and provide opportunities for targeted therapies Notwithstanding these recurrent genomic changes, genome-wide somatic mutations are relatively infrequent in MM.
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