The DNA Damage Response and Inflammation in Cancer

Abstract

Genomic stability in normal cells is crucial to avoid oncogenesis. Accordingly, multiple components of the DNA damage response (DDR) operate as bona fide tumor suppressor proteins by preserving genomic stability, eliciting the demise of cells with unrepairable DNA lesions, and engaging cell-extrinsic oncosuppression via immunosurveillance. That said, DDR sig­naling can also favor tumor progression and resistance to therapy. Indeed, DDR signaling in cancer cells has been consistently linked to the inhibition of tumor-targeting immune responses. Here, we discuss the complex interactions between the DDR and inflammation in the context of oncogenesis, tumor progression, and response to therapy. Significance: Accumulating preclinical and clinical evidence indicates that DDR is intimately connected to the emission of immunomodulatory signals by normal and malignant cells, as part of a cell-extrinsic program to preserve organismal homeostasis. DDR-driven inflammation, however, can have diametrically opposed effects on tumor-targeting immunity. Understanding the links between the DDR and inflammation in normal and malignant cells may unlock novel immunotherapeutic paradigms to treat cancer.

Single-cell analysis of T lymphocytes infiltrating colorectal carcinoma: the dilemma of specificity

“…This particularity increases cancer antigenicity and hence influences tumor surveillance by adaptive immune effector cells as well as the response to immune checkpoint inhibitors (ICIs). 2 , 3 Along this line, the Immunoscore (IS) has been internationally validated for refining the prognosis of CRC. It consists in measuring the density of CD3 + T lymphocytes, and their cytotoxic CD8 + T cell subset, in both the center and invasive margin of the tumor.…”

Immunosurveillance in clinical cancer management

“…At least in some cancers, such a propensity to accumulate mutations is driven by defects in a specific mechanism of DNA repair called mismatch repair (MMR), which is associated with the instability of specific DNA regions called microsatellites. 40 Accordingly, tumors with a molecular diagnosis of defective MMR (dMMR) or elevated (high) microsatellite instability (MSI-H) are exquisitely sensitive to ICIs, 41 which resulted in the FDA approval of pembrolizumab for use in patients with dMMR/MSI-H cancers irrespective of tissue of origin. 42 That said, TMB testing does not account for the immunological alterations imposed by genetic defects other than single nucleotide mutations, such as indels and frameshift mutations.…”

Type I interferon and cancer

“…153 Defects in type I IFN signaling have also been associated with resistance to ICIs targeting cytotoxic T lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1 (PDCD1, best known as PD-1) in preclinical models of melanoma, CRC, and other tumor types. 113,140 In line with this notion, ICIs and other immunotherapeutic agents have been shown to synergize with type I IFN-eliciting interventions in a variety of preclinical settings, including (but not limited to): (1) CRC-bearing mice receiving a PD-1 blocker plus a PARP7 inhibitor, 151 (2) mice with established melanomas, CRCs or mammary tumors receiving focal RT plus a number of different immunotherapeutics, 107,148,149,[154][155][156][157] (3) mammary tumor-bearing mice treated with an HER2 blocker (which at least partially relies on type I IFN signaling) or a TLR3 agonist plus an ICI targeting PD-1, 152,158 and (4) homologous recombination deficient (HRD) mouse mammary and ovarian tumors established in immunocompetent syngeneic hosts and treated with the poly(ADP-ribose) polymerase 1 (PARP1) inhibitor olaparib, which drives potent type I IFN responses, 26 and a PD-1 blocker. 159 That said, type I IFN signaling has also been associated with resistance to immunostimulatory anticancer agents including RT optionally combined with an ICI targeting PD-L1 in various preclinical tumor models, at least in part reflecting the ability of type I IFN to elicit the upregulation of serpin family B member 9 (SERPINB9), a potent cytoprotective factor.…”

“…Importantly, PRRs not only respond to PAMPs, but also to endogenous molecules commonly known as damage-associated molecular patterns (DAMPs). 25 The emission of these danger signals, which include a plethora of proteins, nucleic acids, and lipids that in physiological conditions are physically separated and hence cannot interact with cognate PRRs (e.g., nuclear and mitochondrial nucleic acids), [26][27][28][29] play indeed a key role in determining the immunogenicity of dying cancer cells. 30 (RAP1A).…”