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Review
. 2021 May 1;35(9-10):602-618.
doi: 10.1101/gad.348314.121. Epub 2021 Apr 22.

Interfaces between cellular responses to DNA damage and cancer immunotherapy

Domenic Pilger  1 , Leonard W Seymour  2 , Stephen P Jackson  1
Affiliations
Review

Interfaces between cellular responses to DNA damage and cancer immunotherapy

Domenic Pilger et al. Genes Dev. .

Abstract

The DNA damage response (DDR) fulfils essential roles to preserve genome integrity. _targeting the DDR in tumors has had remarkable success over the last decade, exemplified by the licensing of PARP inhibitors for cancer therapy. Recent studies suggest that the application of DDR inhibitors impacts on cellular innate and adaptive immune responses, wherein key DNA repair factors have roles in limiting chronic inflammatory signaling. Antitumor immunity plays an emerging part in cancer therapy, and extensive efforts have led to the development of immune checkpoint inhibitors overcoming immune suppressive signals in tumors. Here, we review the current understanding of the molecular mechanisms underlying DNA damage-triggered immune responses, including cytosolic DNA sensing via the cGAS/STING pathway. We highlight the implications of DDR components for therapeutic outcomes of immune checkpoint inhibitors or their use as biomarkers. Finally, we discuss the rationale for novel combinations of DDR inhibitors with antagonists of immune checkpoints and current hindrances limiting their broader therapeutic applications.

Keywords: DNA damage response; DNA repair; PARP inhibitors; PD-1; PD-L1; STING; cGAS; immunotherapy.

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Figures

Figure 1.
Figure 1.
DDR inhibitors and their impacts on DSB repair and cell cycle progression. In mammalian cells, four main DSB pathways exist, which operate dependent on the stage of the cell cycle: nonhomologous end-joining (NHEJ), alternative end-joining (alt-EJ), homologous recombination (HR), and single-strand annealing (SSA) (Scully et al. 2019). TOP2i induced DSBs are predominantly repaired via NHEJ, which while being described as “error-prone,” ensures effective repair of broken DNA ends particularly during G0 and in the G1 phase of the cell cycle. DNA-PK is crucial for effective NHEJ, and DNA-PK inhibitors impair DSB repair via NHEJ. TOP1 inhibitors generate single-ended DSBs (seDSBs) in S phase, which require HR for accurate repair. HR is a form of DNA recombination where DNA homology and synthesis can accurately regenerate the sequence surrounding the DSB, facilitated by a sister chromatid as template and therefore restricted to S or G2 (Karanam et al. 2012). DNA damage arising from PARP inhibition also requires HR, since spontaneously occurring SSBs are converted into seDSBs during DNA replication upon PARP inhibitors (PARPis). In addition, PARPi cause mitotic catastrophe and induce DNA replication stress through altering DNA replication fork speed. A fundamental step during HR-mediated repair is DNA end resection, generating ssDNA overhangs that are rapidly covered by RPA and consequently by RAD51. ATR is activated by ssDNA as a result of DNA end resection or DNA polymerase uncoupling from helicase activity during DNA replication. Consequently, ATR inhibitors primarily have impacts during S and G2 phases of the cell cycle. Additionally, ATRi overrides the G2/M cell cycle checkpoint, therefore causing premature entry into mitosis. Importantly, ATM inhibition affects efficient HR, alongside its impact on G1/S and G2/M cell cycle checkpoints in response to DNA damage. Analogous to ATRi and ATMi, WEE1 inhibitors affect the G2/M cell cycle checkpoint. Moreover, WEE1i cause replication stress through dysregulated origin firing and cleavage of DNA replication forks, resulting in DSBs.
Figure 2.
Figure 2.
DNA repair defects and their impacts on cellular immune responses. Defects in DNA repair pathways or DDR components affect innate and adaptive immune responses in various ways. (1) The induction of DSBs via chemotherapeutics or irradiation can lead to micronuclei formation and consequent recognition of cytosolic DNA by cGAS/STING. Deficiencies in genes encoding proteins such as BRCA2, RNase H2, or ATM further augment these effects. (2) Cytosolic DNA can also be a result of aberrant processing of DNA replication intermediates, with several DDR factors limiting either the generation (SAMHD1) or the translocation (RAD51 and RPA) of cytosolic DNA from the nucleus, or degrading DNA once it is present in the cytosol (TREX1). (3) Activation of the cGAS-cGAMP-STING cascade leads to IRF3 and NFκB transcriptional programs, resulting in expression of IFN and ISGs, therefore inducing strong innate immune responses. (4) In contrast, MMR defects can lead to adaptive immune responses through increased somatic mutations and consequent synthesis of neoantigens. When presented by MHC molecules at the cell surface, neoantigens elicit a strong T-cell response, dependent on the immunogenicity of the neoantigen.
Figure 3.
Figure 3.
Innate and adaptive immune responses in cancer. In recent years, the concept of cancer immunoediting evolved from traditional views of the immune system constantly surveying and eliminating transformed cells in order to counteract cancer development (immunosurveillance) (Keast 1970). Cancer immunoediting unifies observations of the immune system promoting tumor outgrowth with reports of immunosurveillance, highlighting the dual functions of the immune system during tumor development (Schreiber et al. 2011). The cancer immunoediting concept consists of three phases: elimination, equilibrium, and escape. In the elimination phase, components of both the innate and adaptive immune response recognize and destroy cells undergoing oncogenesis. Elimination is promoted by a number of signaling molecules such as type I and type II IFNs and is executed via the interplay of a subset of immune cells such as CD8+ T cells, dendritic cells (DCs), natural killer cells (NKs), natural killer T cells (NKTs), proinflammatory (“M1”) macrophages, and others (Mittal et al. 2014). Notably, the DDR participates in this process, since DNA damage induction in tumors cells results in up-regulation of ligands for the receptors NKG2D and DNAM-1, therefore stimulating cytotoxicity of NK and CD8+ T cells in addition to IFN-γ secretion (Gasser et al. 2005; Croxford et al. 2013). Moreover, radiotherapy-induced DNA damage, and consequent cell death due to uncomplete DNA repair, stimulates cross-presentation by dendritic cells and increased lymphocyte influx, thus further contributing to cancer cell elimination (Deng et al. 2014b; Samstein and Riaz 2018; Cornel et al. 2020; Cheng et al. 2021). Paradoxically, TNF-α has both antitumor and tumor-promoting activity. When secreted by macrophages and innate immune cells, TNF-α induces cancer cell elimination, whereas chronic inflammation promoted by TNF-α signaling can drive carcinogenesis (Balkwill 2009; Charles et al. 2009). In the equilibrium phase, the adaptive immune system holds the tumor in a dormant state with cancer cells resisting constant immune recognition through genetic and epigenetic changes in antigen presentation and immunosuppressive pathways. Cancer cells achieve immune evasion by various mechanisms, including loss of tumor antigens or factors involved in antigen presentation, such as type I HLA (MHC) function, expression of inhibitory ligands (e.g., PD-L1 and CTLA-4), secretion of immunosuppressive cytokines (IL-10, TGF-β), and recruitment of tumor-associated macrophages (TAMs) and regulatory T cells (Tregs). These scenarios result in the inability of innate and adaptive immune cells to recognize and appropriately respond to oncogenic cells, therefore facilitating tumor progression (escape phase) (Vinay et al. 2015).
Figure 4.
Figure 4.
Principles of immune checkpoint inhibitors for cancer therapy. As described in Figure 3, during the escape phase of the immunoediting concept, tumor cells evade immune recognition and destruction by active immunosuppression in the tumor. A milestone for the field of immune checkpoint inhibitors was the report in which melanoma patients treated with an antibody _targeting the T-cell checkpoint protein CTLA-4 showed significantly improved survival compared with the control group (Hodi et al. 2010). This suggested that _targeting suppressive immune checkpoints can improve overall survival in melanomas, indicating that a patient's immune system has capabilities to control tumor growth once immunosuppressive signals are overcome. Since this pharmacological approach _targets the patient's immune system rather than the tumor itself, a new field for clinical research arose. CTLA-4 is a surface receptor on T cells. To acquire effector function, a T-cell recognizes its compatible antigen, presented by MHC molecules of an antigen-presenting cell (APC), via its T-cell receptor (TCR). However, this initial recognition is insufficient, with binding of the CD28 T cell receptor to B7 molecules (CD80 or CD86 ligand) on APCs serving as crucial costimulatory signals to adequately prime T cells. CTLA-4 translocates to the cell surface once T cells are activated, where it binds CD80 and CD86 with higher affinity than CD28, therefore dampening T-cell activation (Walunas et al. 1994; Krummel and Allison 1995). Moreover CTLA-4 expression by Tregs is crucial for their immune suppressive functions, potently binding CD80/CD86 ligands on APCs and therefore preventing T-cell activation (Takahashi et al. 2000; Wing et al. 2008). Following its initial success in clinical trials, the CTLA-4 antibody ipilimumab was FDA approved in 2011 for treating melanomas. PD-1 represents another inhibitory receptor present on T cells, while its ligands PD-L1 and PD-L2 can be expressed by various cell types, including APCs and malignant cells, predominantly after exposure to inflammatory cytokines such as IFN-γ. Engagement of PD-L1 with its receptor PD-1 interferes with TCR signaling, therefore limiting T-cell responses toward tumor cells (Freeman et al. 2000; Dong et al. 2002). Following this rational, antibodies _targeting PD-1/PD-L1 have provoked clinical benefits in various types of cancers, warranting FDA approval of pembroluzimab and nivolumab (both PD-1 antagonists) in 2014. Unlike CTLA-4, PD-1/PD-L1 does not interfere with costimulation during the T-cell activation, suggesting that combination therapy of CTLA-4 and PD-1/PD-L1 antibodies could have synergistic therapeutic effects. Regaining T-cell activation, by blocking inhibitory signals during costimulation via CTLA-4 antibodies, could drive increased PD-L1 expression in tumor cells, making them particularly susceptible to PD-1/PD-L1 checkpoint blockade (Sharma and Allison 2015).
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References

    1. Ablasser A, Goldeck M, Cavlar T, Deimling T, Witte G, Röhl I, Hopfner KP, Ludwig J, Hornung V. 2013. cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING. Nature 498: 380–384. 10.1038/nature12306 - DOI - PMC - PubMed
    1. Ablasser A, Hemmerling I, Schmid-Burgk JL, Behrendt R, Roers A, Hornung V. 2014. TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner. J Immunol 192: 5993–5997. 10.4049/jimmunol.1400737 - DOI - PubMed
    1. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Borresen-Dale AL, et al. 2013. Signatures of mutational processes in human cancer. Nature 500: 415–421. 10.1038/nature12477 - DOI - PMC - PubMed
    1. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, de Wit M, et al. 2017. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 377: 1919–1929. 10.1056/NEJMoa1709937 - DOI - PubMed
    1. Balkwill F. 2009. Tumour necrosis factor and cancer. Nat Rev Cancer 9: 361–371. 10.1038/nrc2628 - DOI - PubMed

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