Grant: Project Grant

Clear cell renal cell carcinoma (ccRCC) is the 10th most common cancer in Canada and among the top 10 worldwide. Immunotherapies represent first-line treatment regimens for patients with metastatic ccRCC. However, most of these patients fail to respond, making it critical to understand mechanisms underlying this immune evasion. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon response cGAMP interactor 1 (STING)-mediated innate immune response plays an important role in modulating the tumor microenvironment, which influences the efficacy of immunotherapies. Activation of this response has potent anti-tumor activities, however if activated chronically, it can lead to inflammation-driven tumorigenesis and immune evasion. As this response can be activated by DNA replication stress, which can be indirectly induced by adverse conditions in tumor microenvironment, it is critical to understand the relationship between this response and replication stress. This proposal aims to elucidate how the activating signal co-integrator 1 complex (ASCC), a multifunctional complex, connects replication stress to the cGAS-STING-mediated innate immune response in ccRCC cells. Knowledge gained from this proposal will be critical to future efforts focusing on exploiting the replication stress response to improve immunotherapies for ccRCC.