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.

Comprehensive Analyses Identify APOBEC3A as a Genomic Instability-Associated Immune Prognostic Biomarker in Ovarian Cancer

“…More importantly, PLCH1 was also found to be exclusively mutated with TP53, which illustrated that PLCH1 might have similar functions with TP53 in the same pathway. Additionally, the DDR pathway is acknowledged to maintain the genome stability when DNA damage occurs, which has been found to have a close correlation with response to ICB therapy (71)(72)(73). Also, APOBEC3A expression was reported to cause DNA damage responses of cancers (74,75).…”

Managing Malignant Pleural Mesothelioma in the Age of Personalized Medicine: Where Are We and What Is Still Missing?

“…The observation that the tumor mutational burden (TMB) is extremely low in MPM sustains the rationale of the opinion paper presented by H. Brossel et al The authors reasoned that the stimulation of mechanisms of the DNA damage tolerance (DDT) pathways could increase the frequency of non-synonymous mutations that are, in turn, processed and presented by the MHC-I complex. Thus, they proposed to exploit a transient activation of the error-prone DDT to generate neoantigens while preserving a fully competent antitumor immune response [ 4 ]. Another option to efficiency target MPM is discussed in the work published by Johnson B. et al, which shows that the combination of small molecule inhibitor-targeting agents of survivin and FAK with tumor-suppressor miRNA mimics might constitute promising efficacy as a potential combinational treatment [ 5 ].…”