SMARCAL1 is a dual regulator of innate immune signaling and PD-L1 expression that promotes tumor immune evasion

The Rosalind and Morris Goodman Cancer Institute Frontiers in Cancer Research Lecture Series is pleased to welcome Giuseppe Leuzzi, Ph.D., Principal Investigator | Functional Genomics of Cancer Immunity. IFOM, The AIRC Institute of Molecular Oncology, Milan, Italy.

The seminar will take place on Wednesday, May 7,2025 at 2:00pm in the GCI Karp Room 501.

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.

Bio:

Giuseppe studied Molecular and Cell Biology at the University of Rome Tor Vergata, earning his B.Sc. and then M.Sc. with honors. He completed his Ph.D. in Genetics and Cell Biology at the Italian National Institute of Health in the laboratory of Dr. Annapaola Franchitto, focusing on DNA damage response (DDR). His doctoral work identified WRNIP1 as a novel factor cooperating with BRCA2 to prevent chromosomal instability and characterized the role of the WRN helicase in replication stress response. He also investigated the interaction between Mismatch Repair and Base Excision Repair in human gastric cancer, advancing the understanding of genome stability and cancer biology. In 2017, Giuseppe joined Prof. Alberto Ciccia’s laboratory at Columbia University as a postdoctoral researcher, supported by AICF and AIRC fellowships. There, he integrated DDR studies with cancer immunology, developing CRISPR-Cas9 screening strategies to identify DDR factors impacting cancer immunity and potential therapeutic targets for immunotherapy. In 2025, Giuseppe established his independent research group at IFOM in Milan, Italy—the Functional Genomics of Cancer Immunity laboratory—where he investigates how DNA repair mechanisms and genomic instability influence cancer immunity and immunotherapy responses.