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      DNA Damage Response and Immune Defense

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          Abstract

          DNA damage is the cause of numerous human pathologies including cancer, premature aging, and chronic inflammatory conditions. The DNA damage response (DDR), in turn, coordinates DNA damage checkpoint activation and promotes the removal of DNA lesions. In recent years, several studies have shown how the DDR and the immune system are tightly connected, revealing an important crosstalk between the two of them. This interesting interplay has opened up new perspectives in clinical studies for immunological diseases as well as for cancer treatment. In this review, we provide an overview, from cellular to molecular pathways, on how DDR and the immune system communicate and share the crucial commitment of maintaining the genomic fitness.

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          Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.

          Naiyer A Rizvi, Matthew Hellmann, Alexandra Snyder … (2015)
          Immune checkpoint inhibitors, which unleash a patient's own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used whole-exome sequencing of non-small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti-PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti-PD-1 therapy. Copyright © 2015, American Association for the Advancement of Science.
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            Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

            Dung Le, Jennifer N. Durham, Kellie N Smith … (2017)
            The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers' tissue of origin.
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              Immunity, inflammation, and cancer.

              Sergei I. Grivennikov, Florian Greten, Michael Karin (2010)
              Inflammatory responses play decisive roles at different stages of tumor development, including initiation, promotion, malignant conversion, invasion, and metastasis. Inflammation also affects immune surveillance and responses to therapy. Immune cells that infiltrate tumors engage in an extensive and dynamic crosstalk with cancer cells, and some of the molecular events that mediate this dialog have been revealed. This review outlines the principal mechanisms that govern the effects of inflammation and immunity on tumor development and discusses attractive new targets for cancer therapy and prevention. 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 12 October 2020
                Publication date Collection: October 2020
                Volume: 21
                Issue: 20
                Electronic Location Identifier: 7504
                Affiliations
                Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milan, Italy; laura.mannarino@ 123456marionegri.it
                Author notes
                Author information
                https://orcid.org/0000-0003-4438-0554
                https://orcid.org/0000-0002-0290-4228
                Article
                Publisher ID: ijms-21-07504
                DOI: 10.3390/ijms21207504
                PMC ID: 7588887
                PubMed ID: 33053746
                SO-VID: 635a06cc-bf03-4a7a-b97e-f4f955b86bb5
                Copyright © © 2020 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 23 September 2020
                Date accepted : 10 October 2020
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular biology
                Keywords: dna damage response,dna repair,immune defense,immune signalling,innate immunity,cancer
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: dna damage response, dna repair, immune defense, immune signalling, innate immunity, cancer

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