Delineating how nucleic acid sensing in tumor cells regulate anti-tumor immune responses

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Project Summary Impaired DNA damage responses can lead to genomic and chromosomal instability in cancer. High levels of chromosomal instability have been associated with increased mutation rates, metastasis, and immune evasion in cancer. Paradoxically however, DNA- damaging chemo- and radio-therapies can trigger anti-tumor inflammatory responses. How DNA damage in tumor cells regulate both anti-and pro-tumor immune responses within the tumor microenvironment (TME) represents an important knowledge gap. The Greenberg group (Project 1) has shown that DNA damage in cancer cells activate cytosolic DNA sensing pathway regulated by cyclic AMP-GMP synthase (cGAS) and stimulator of interferon genes (STING), as well as an RNA sensing pathway regulated by retinoic acid-inducible gene I (RIG-I). Activation of these nucleic acid-sensing pattern recognition receptors (PRRs) induces type I interferon (IFN-I) – a cytokine that promotes protective immunity against pathogens. Cytosolic nucleic acids can also activate inflammasomes to secrete interleukin (IL)-1β and - 18, which have both pro- and anti-tumor effects. Intriguingly, our preliminary data suggest that inflammasome activation in response to DNA damage promotes tumor growth in an ovarian cancer model. Antigen presenting cells (APCs) are key mediators of immune responses and our recent work have identified novel subsets of APCs and their regulation by interferons in the TME. In this proposal, we will examine the hypothesis that the outcome of tumor control is driven by the opposing anti- and pro-tumor effects of IFN-I and IL-1β/ IL-18 on APCs in response to cancer cell DNA damage. Towards this goal, we will closely collaborate with Projects 1 (Greenberg) and 2 (Lampson/Discher) and rely on novel genetic (MAC core) and chemical (Chemical Biology Core) tools. The three specific aims will examine the mechanisms underlying IFN-I-dependent anti-tumor (Aim 1) and inflammasome dependent pro-tumor (Aim 2) effects of cancer cell DNA damage, and provide proof-of-concept for targeting these pathways for combinatorial immunotherapy (Aim 3). These findings will provide fundamental insights into immune mechanisms underlying how genome instability regulates immune responses in tumor and provide a foundation for future attempts to target these pathways for cancer therapy.