High-throughput functional interrogation of the impact of DNA repair gene mutations on anti-tumor immunity

Dr. Alberto Ciccia is investigating how to take advantage of tumor genome instability, which arises due to mutations in DNA repair genes, to improve immunotherapy outcomes for patients. Cancer immunotherapies have resulted in robust and durable responses in numerous cancer types. Nevertheless, since tumors can become resistant to immunotherapy via several mechanisms, only a fraction of current patients gain the full benefit of these treatments. Recent studies have shown that genome instability in cancer cells can enhance immune responses against tumors by inducing cancer-intrinsic innate immunity via DNA damage response (DDR) signaling pathways; however, it's unknown which specific DDR factors regulate innate immune responses and boost anti-tumor immunity. Furthermore, in DDR genes, there are more than 50,000 known single nucleotide variants (SNVs)—which have a single mutated letter in their DNA code—but their impact on patient responses to immunotherapy remains undetermined. Therefore, Dr. Ciccia's goal is to (1) identify DDR factors that modulate hw ell the immune system recognizes tumors using newly developed genetic screens that monitor markers of innate immune signaling and checkpoint immunotherapy response; and (2) determine how cancer-associated SNVs found in DDR genes affect immunotherapy responses using an innovative editing and screening platform to generate SNVs within cells. Overall, Dr. Ciccia aims to uncover novel factors that could be targeted to improve immune-based cancer treatments and provide unprecedented insights into the impact of SNVs on anti-tumor immunity, thus paving the way for the development of SNV-targeted cancer therapies.