Activation of DNA Damage Tolerance Pathways May Improve Immunotherapy of Mesothelioma

Our plain-English summary of Activation of DNA Damage Tolerance Pathways May Improve Immunotherapy of Mesothelioma, by H. Brossel, A. Fontaine, C. Hoyos, et al (Cancers, 2021).

The study

• Authors: H. Brossel, A. Fontaine, C. Hoyos, M. Jamakhani, M. Willems, M. Hamaidia, L. Willems
• Journal: Cancers
• Published: 2021;13(13)
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This article is an opinion paper; the authors did not enroll patients or study asbestos exposure. The authors proposed a way to improve immunotherapy of malignant mesothelioma with immune checkpoint inhibitors (nivolumab and ipilimumab). Their reasoning was that these drugs depend on tumors carrying mutations that produce abnormal protein fragments (neoantigens) the immune system can recognize, and mesothelioma tumors carry relatively few mutations. Using publicly available tumor data from mesothelioma patients and other cancer types in the TCGA database, they reported a median of 0.726 somatic mutations per megabase in mesothelioma tumors. They proposed giving DNA-damaging chemotherapy drugs such as cisplatin at suboptimal doses or on adjusted schedules. The aim would be to briefly switch on error-prone "DNA damage tolerance" pathways in tumor cells and create new mutations while sparing immune cells. The authors believed this would increase the effectiveness of checkpoint inhibitors. They acknowledged that low doses might fail and be followed by drug resistance and tumor escape. They also acknowledged that overlapping DNA repair and tolerance pathways could limit new mutations. The paper put forward the idea for investigation and did not test it.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: opinion paper proposing a treatment strategy, with a plot of publicly available tumor genome data (TCGA)
• Who was studied: No patients were enrolled. The authors analyzed publicly available tumor genome data from mesothelioma patients and from other cancer types in the TCGA database.
• Exposure: No asbestos exposure was studied (asbestos is mentioned only as background). The proposal concerns low (suboptimal) doses or adjusted delivery of DNA-damaging chemotherapy such as cisplatin, combined with immune checkpoint inhibitors.
• Main results:
  • In TCGA data on mesothelioma tumors, the median number of somatic mutations was 0.726 per megabase.
  • In the authors' plot of TCGA data across cancer types, mesothelioma showed a low tumor mutational burden.
• The authors' conclusion: The authors proposed briefly activating error-prone DNA damage tolerance pathways to create somatic mutations and increase the tumor peptides presented to the immune system. They believed this would improve the effectiveness of immune checkpoint blockade.
• Limitations the authors state:
  • Low or fine-tuned drug doses might not work well enough and could be followed by chemoresistance and tumor escape.
  • Overlapping DNA repair and DNA damage tolerance pathways could limit how many new somatic mutations arise.

Topics

Medical terms in this study, explained in our Lexicon: Immunotherapy, Mesothelioma, checkpoint inhibitors, Nivolumab (Opdivo), CTLA-4, Ipilimumab (Yervoy), Overall Survival, Median Overall Survival.

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