Principal Investigator | Functional Genomics of Cancer Immunity, IFOM, The AIRC Institute of Molecular Oncology, Milan, Italy
Disarming tumor immune evasion by targeting DNA repair pathways
Host: G. Del Sal
Abstract
The extensive genomic and epigenomic instability of tumor cells can trigger cancer cell-intrinsic innate immune responses that promote tumor rejection. However, cancer cells often evade these responses by overexpressing immune checkpoint regulators, such as PD-L1. The cellular factors regulating these processes remain largely unknown. Using unbiased CRISPR-Cas9 screens of DNA repair and chromatin regulators, we identified the SNF2-family DNA translocase SMARCAL1 as a factor that promotes tumor immune evasion through a dual mechanism involving both the suppression of innate immune signaling and the induction of PD-L1-mediated immune checkpoint responses. Mechanistically, SMARCAL1 limits endogenous DNA damage, thereby suppressing cGAS-STING-dependent signaling during cancer cell growth. Simultaneously, it cooperates with the AP-1 family member JUN to maintain chromatin accessibility at a PD-L1 transcriptional regulatory element, promoting PD-L1 expression in cancer cells. SMARCAL1 loss hinders the ability of tumor cells to induce PD-L1 in response to genomic instability, enhances anti-tumor immune responses, and sensitizes tumors to immune checkpoint blockade in a mouse melanoma model. Collectively, these findings identify SMARCAL1 as a promising therapeutic target for cancer immunotherapy.
International Seminar Programme
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