Article (Scientific journals)
Activation of DNA Damage Tolerance Pathways May Improve Immunotherapy of Mesothelioma
Brossel, Hélène; Fontaine, Alexis; Hoyos, Clotilde et al.
2021In Cancers, 13, p. 3211
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Keywords :
mesothelioma; tolerance to DNA damage; DNA damage response; chemoresistance; immunotherapy; immune checkpoint inhibitor
Abstract :
[en] 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.
Disciplines :
Oncology
Author, co-author :
Brossel, Hélène ;  Université de Liège - ULiège > GIGA Cancer - Cellular and Molecular Epigenetics
Fontaine, Alexis ;  Université de Liège - ULiège > GIGA Cancer - Cellular and Molecular Epigenetics
Hoyos, Clotilde ;  Université de Liège - ULiège > GIGA Cancer - Cellular and Molecular Epigenetics
Jamakhani, Majeed ;  Université de Liège - ULiège > GIGA Cancer - Cellular and Molecular Epigenetics
Willems, Mégane  ;  Université de Liège - ULiège > GIGA Cancer - Cellular and Molecular Epigenetics
Hamaïdia, Malik  ;  Université de Liège - ULiège > GIGA Cancer - Cellular and Molecular Epigenetics
Willems, Luc  ;  Université de Liège - ULiège > GIGA Cancer - Cellular and Molecular Epigenetics
Language :
English
Title :
Activation of DNA Damage Tolerance Pathways May Improve Immunotherapy of Mesothelioma
Publication date :
2021
Journal title :
Cancers
eISSN :
2072-6694
Publisher :
Multidisciplinary Digital Publishing Institute (MDPI), Switzerland
Volume :
13
Pages :
3211
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
Télévie [BE]
Belgian Foundation Against Cancer [BE]
ULg FSR - Université de Liège. Fonds spéciaux pour la recherche [BE]
Fonds Léon Fredericq [BE]
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since 17 January 2022

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