Characterization of the functions of the DNA translocase SMARCAL1 in anti-tumor immunity

The DNA damage response (DDR) is a cellular network that safeguards genomic stability. When compromised, genomic DNA can accumulate in the cytoplasm, triggering innate immune signaling events culminating in the expression of interferon (IFN) and IFN-stimulated genes. While IFN signaling can increase immune responses towards genomically unstable tumor cells by facilitating tumor antigen presentation and promoting the recruitment of cytotoxic T cells that mediate tumor rejection, it can simultaneously favor tumor immune evasion through the expression of PD-L1, an immune checkpoint protein that interacts with the PD-1 receptor on cytotoxic T cells, inhibiting their ability to kill cancer cells. Immune checkpoint blockade (ICB) therapies, which disrupt the interaction between PD-L1 and PD-1, have shown remarkable efficacy in reactivating T cells and eliciting robust anti-tumor responses . However, at present, only a small fraction of patients gain the full benefit of these treatments due to resistance mechanisms acquired by tumor cells. Given the complex interplay between the DDR, IFN signaling and the PD-L1-dependent immune checkpoint, elucidating these intricate relationships is crucial for developing more potent cancer immunotherapies. In preliminary work, we have conducted genetic screens to identify factors that regulate both innate immune signaling and PD-L1 levels in cancer cells. This work uncovered the SNF2-family DNA translocase SMARCAL1 as a DDR factor that favors tumor immune evasion by a dual mechanism that involves both the suppression of innate immune signaling and the induction of PD-L1-mediated immune checkpoint responses. The main goals of this proposal are to elucidate the molecular mechanisms by which SMARCAL1 suppresses anti-tumor immune responses and identify other DDR factors that function analogously to SMARCAL1. In particular, we propose 1) To define the mechanisms by which SMARCAL1 suppresses innate immune signaling in cancer cells; 2) To define the mechanisms by which SMARCAL1 regulates PD-L1 expression in cancer cells; 3) To characterize novel DDR factors that suppress innate immunity and promote PD-L1 expression in cancer cells. Our approach will utilize a combination of cellular, molecular and biochemical assays, high-throughput genetic screens, and studies in animal models. We expect that this work will offer new insights into potential targets that could be exploited for improving the efficacy of cancer immunotherapies. Project Number: 1R01CA304254-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Alberto Ciccia | Institution: COLUMBIA UNIVERSITY HEALTH SCIENCES, NEW YORK, NY | Award Amount: $630,089 | Activity Code: R01 | Study Section: Basic Cancer Immunobiology Study Section[BCIB] View on NIH RePORTER: https://reporter.nih.gov/project-details/11366023