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Targeting the DNA damage response in immuno-oncology: developments and opportunities

Nature Reviews Cancer volume 21, pages 701–717 (2021)Cite this article

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Abstract

Immunotherapy has revolutionized cancer treatment and substantially improved patient outcome with regard to multiple tumour types. However, most patients still do not benefit from such therapies, notably because of the absence of pre-existing T cell infiltration. DNA damage response (DDR) deficiency has recently emerged as an important determinant of tumour immunogenicity. A growing body of evidence now supports the concept that DDR-targeted therapies can increase the antitumour immune response by (1) promoting antigenicity through increased mutability and genomic instability, (2) enhancing adjuvanticity through the activation of cytosolic immunity and immunogenic cell death and (3) favouring reactogenicity through the modulation of factors that control the tumour–immune cell synapse. In this Review, we discuss the interplay between the DDR and anticancer immunity and highlight how this dynamic interaction contributes to shaping tumour immunogenicity. We also review the most innovative preclinical approaches that could be used to investigate such effects, including recently developed ex vivo systems. Finally, we highlight the therapeutic opportunities presented by the exploitation of the DDR–anticancer immunity interplay, with a focus on those in early-phase clinical development.

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Fig. 1: Genome integrity-related dysfunctions and molecular determinants of cytosolic immunity.
Fig. 2: The DNA damage response shapes the tumour–immune cell interface.
Fig. 3: Therapeutic strategies to exploit the DNA damage response–immunity interplay in the clinic.

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Acknowledgements

The authors thank Y. L. Lin and H. Técher for their careful reading of the manuscript and insightful comments. The work in the laboratory of S.P.-V. is supported by programme grants from ATIP-Avenir INSERM / La Ligue Nationale Contre le Cancer, SIRIC SOCRATE-2 (INCa-DGOS-INSERM_12551), Cancéropôle Ile-de-France (2017-1-EMERG-72) and Association pour la Recherche contre le Cancer (ARC PGA1 RF 20190208576). R.M.C. received funding from Fondation Bettencourt-Schueller, Fondation des Treilles, Fondation Philanthropia-Lombard Odier, Institut Servier, and Cancéropôle Ile-De-France.

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Authors and Affiliations

  1. ATIP-Avenir Group, Inserm Unit U981, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France

    Roman M. Chabanon & Sophie Postel-Vinay

  2. The CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, UK

    Roman M. Chabanon & Christopher J. Lord

  3. Equipe Labellisée Ligue Nationale contre le Cancer, Inserm Unit U1015, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France

    Mathieu Rouanne

  4. Département d’Urologie, Hôpital Foch, Université Versailles-Saint-Quentin-en-Yvelines, Université Paris-Saclay, Suresnes, France

    Mathieu Rouanne

  5. Drug Development Department (DITEP), Gustave Roussy Cancer Campus, Villejuif, France

    Jean-Charles Soria & Sophie Postel-Vinay

  6. Faculté de Médicine, Université Paris-Sud, Université Paris-Saclay, Le Kremlin Bicêtre, France

    Jean-Charles Soria & Sophie Postel-Vinay

  7. Equipe Labellisée Ligue contre le Cancer, Institut de Génétique Humaine, CNRS, Université de Montpellier, Montpellier, France

    Philippe Pasero

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Contributions

R.M.C. and M.R. researched data for the article. R.M.C., M.R. and S.P.-V. contributed substantially to discussion of the content. R.M.C., M.R. and S.P.-V. wrote the article. All authors contributed to reviewing and editing the manuscript before submission.

Corresponding author

Correspondence to Sophie Postel-Vinay.

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Competing interests

R.M.C., M.R. and P.P. have no conflicts of interest or financial interests to disclose. C.J.L. is a named inventor on patents describing the use of DNA repair inhibitors and stands to gain from their use as part of the Institute of Cancer Research Rewards to Inventor scheme. C.J.L. has received research funding from AstraZeneca, Merck KGaA, Artios and Pfizer, has received consultancy and/or advisory fees from Astra Zeneca, Merck KGaA, Artios, Tango and GLG, and is a shareholder of OviBio and Tango. J.-C.S. has received consultancy fees from Relay Therapeutics, is a shareholder of AstraZeneca, Gritstone and Daiichi Sankyo, and is a member of the Hookipa board of directors. S.P.-V. has received research funding from Merck KGaA, Boehringer Ingelheim and Roche for unrelated research projects. As part of the Drug Development Department (DITEP), S.P.-V. is a principal investigator or a subinvestigator on clinical trials by Abbvie, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca, Aveo, Bayer Healthcare AG, Bbb Technologies BV, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Chugai Pharmaceutical Co., Clovis Oncology, Daiichi Sankyo, Debiopharm S.A., Eisai, Eli Lilly, Exelixis, Forma, Gamamabs, Genentech Inc., Glaxosmithkline, H3 Biomedicine Inc., Hoffmann La Roche AG, Innate Pharma, Iris Servier, Janssen Cilag, Kyowa Kirin Pharmaceutical Development Inc., Loxo Oncology, Lytix Biopharma AS, Medimmune, Menarini Ricerche, Merck Sharp & Dohme-Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology NV, Oncoethix, Onyx Therapeutics, Orion Pharma, Oryzon Genomics, Pfizer, PharmaMar, Pierre Fabre, Roche, Sanofi Aventis, Taiho Pharma, Tesaro Inc. and Xencor. S.P.-V. has participated in advisory boards for Merck KGaA.

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Nature Reviews Cancer thanks L.A. Byers, who co-reviewed with C. Gay; G.M. Li, who co-reviewed with Y. Huang; and E. Parkes for their contribution to the peer review of this work.

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Supplementary information

Glossary

Genomic instability

Considered as a hallmark of cancer, a direct consequence of DNA damage response and DNA replication deficiencies, which promote mutagenesis and tumour progression.

Tumour cell-autonomous responses

Set of intrinsic cellular processes that occur within a tumour cell independently of the presence or interaction with other cells.

Mismatch repair

(MMR). DNA damage response pathway that corrects mismatched nucleotides in otherwise complementary paired DNA strands.

Adjuvanticity

The capacity of a cell to produce immunogenic adjuvants; that is, endogenous (usually non-specific) molecules that stimulate, activate, potentiate or modulate the antitumour immune response at either the cellular level or the humoral level.

Mutational signatures

Combinations of mutations that arise from and are characteristic of specific endogenous or exogenous mutagenic processes, such as mutagenesis secondary to DNA damage response or chromatin remodelling defects, or exposure to DNA-damaging agents.

Tumour neoantigens

Tumour-specific antigens that derive from non-synonymous somatic mutations exclusively present in a tumour.

Tumour mutational burden

(TMB). The total number of mutations carried by a tumour at a given time, classically determined by whole-genome sequencing or whole-exome sequencing.

Homologous recombination

(HR). DNA damage response pathway that mediates high-fidelity repair of DNA lesions, notably double-strand breaks, using a sister chromatid as a template during the S and G2 phases of the cell cycle.

Base-excision repair

DNA damage response pathway that removes single-base lesions caused by alkylating agents or reactive oxygen species.

Nucleotide-excision repair

DNA damage response pathway that removes large DNA adducts (such as those caused by exposure to UV light) or base modifications that results in distortion of the DNA double helix using the opposite strand as a template for repair.

Chromatin remodelling complexes

ATP-dependent protein complexes that modify the chromatin structure to regulate gene expression and facilitate DNA repair.

Replication stress response

Series of molecular events that occur when a cell is subjected to replication stress, which corresponds to the non-physiological and persistent slowing down or stalling of replication forks — often caused by lesions in the DNA undergoing replication.

cGAS–STING pathway

Cytosolic DNA-sensing pathway that functions to detect pathogen-derived or damage-derived DNA fragments in the cytosol, and consequently triggers a cell-autonomous innate immune response.

Pattern recognition receptors

Innate immune receptors capable of recognizing pathogen-associated molecular patterns or host-derived damage-associated molecular patterns.

Inflammasome

Multiprotein cytosolic complex that mediates the activation of a caspase 1-dependent proinflammatory response characterized by the production of IL-1β and IL-18.

Immunogenic cell death

(ICD). Peculiar form of cell death characterized by the production of damage-associated molecular patterns that elicit an immunostimulatory response.

Micronuclei

Cytosolic nuclear structures formed outside the primary nucleus, consisting of nucleus-derived DNA isolated from the rest of the cytosol by a nuclear envelope.

Type I interferon

Class of secreted proteins involved in the activation of cell-autonomous innate immune pathways that stimulate natural killer cell and T cell function.

Non-homologous end joining

Error-prone DNA damage response pathway that mediates repair of DNA double-strand breaks by rejoining DNA ends without reliance on a homologous template.

Interstrand crosslink repair

DNA damage response pathway involved in the processing of interstrand crosslinks, those DNA lesions caused by platinum-based chemotherapies that block DNA replication and/or transcription due to the formation of a covalent bond between DNA bases on opposite strands of DNA.

Damage-associated molecular patterns

Stimuli produced as a result of cellular stress in dying or damaged cells, which often triggers an immunostimulatory response through the activation of various pattern recognition receptors.

Chromosomal instability

(CIN). Phenotype referring to a higher than normal rate of chromosome mis-segregation during mitosis, which often results in structural abnormalities (for example, deletions, inversions or translocations), and numerical abnormalities (for example, copy number alterations or aneuploidy).

Alternative lengthening of telomeres

A recombination-based mechanism that allows telomere length maintenance in the absence of telomerase activity.

Senescence-associated secretory phenotype

(SASP). Phenotype of senescent cells characterized by the secretion of a variety of cytokines, chemokines and other soluble factors that promote inflammation.

Abscopal responses

Therapeutic responses induced by radiotherapy when irradiation of tumour cells at the primary tumour site produces a systemic response and biologically relevant changes in distant metastatic sites, which may or may not have been irradiated themselves.

Synthetic lethality

Concept illustrating the cell death that results from combined inactivation or inhibition of two genes or gene products that are non-lethal when inactivated individually.

Window-of-opportunity

Clinical trial in which treatment-naive patients receive one or more investigational cancer treatments between their cancer diagnosis and standard treatment (essentially surgery), allowing the collection of tumour biopsy samples before and after treatment.

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Chabanon, R.M., Rouanne, M., Lord, C.J. et al. Targeting the DNA damage response in immuno-oncology: developments and opportunities. Nat Rev Cancer 21, 701–717 (2021). https://doi.org/10.1038/s41568-021-00386-6

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