Abstract 586: Tumor cell-intrinsic PD-1 activation drives therapeutic resistance in colorectal cancer cells

Abstract Background/Aim: Despite advancements in diagnosis and treatment, advanced CRC remains a formidable treatment challenge with limited therapeutic options because these tumors are resistant to chemo-, radio- and targeted-therapies. Emerging research shows that the presence of tumor cell-intrinsic PD-1 (ciPD-1) in various tumor types is involved in tumorigenicity and therapy-refractory disease. For example, ciPD-1 promotes tumor growth in melanoma and liver cancer, but in lung cancer, ciPD-1 exhibits tumor-suppressive behavior. These findings highlight the intriguing possibility that ciPD-1 may exert context specific functions within the tumor, beyond its well-known role in immune response suppression. Consequently, the present study addressed the pressing need to explore the effects of immune checkpoint inhibitors within broader tumor context and tumor microenvironment. We have established drug-resistant CRC cells and found that ciPD-1 was upregulated in these cells. This, together with an observation that ciPD-1-mediated survival signaling pathways was activated in CRC patient populations, prompted us to investigate the role of ciPD-1 in regulation of therapeutic resistance in CRC in the absence of immune cells. Methods: We evaluated the clinicopathological relevance of ciPD-1 and its correlation with disease progression in CRC samples from clinical cohorts. Monoclonal antibody inhibition and siRNA interference methods were used to characterize the functional roles of ciPD-1 in regulating therapeutic resistance in CRC. The gene expression profiles of PD-1-High and PD-1-Low patient groups retrieved from clinical cohorts were compared to identify ciPD-1-medatied survival pathways in CRC patients. Results: We found that ciPD-1 had a critical role in regulating CRC tumorigenicity and survival outcomes. Tumors with high expression levels of ciPD-1 also showed higher mutation rate and levels of microsatellite instability. Exposing CRC cells to chemotherapy, radiation, and nutrient deprivation increased ciPD-1 levels. In line with these observations, drug-resistant CRC cells also expressed higher levels of ciPD-1. The inhibition of ciPD-1 in CRC cells by monoclonal antibody or siRNA interference decreased cell proliferation and self-renewal rates, while enhancing treatment efficacy. Conclusion: Our studies reveal that CRC cells increase ciPD-1 expressions in response to drug treatment and targeting ciPD-1-mediated survival pathways can delay the onset of drug resistance and promote therapeutic sensitiveness in CRC cells. Citation Format: Ho Kit Mok, Donald Yapp, Isabella Tai. Tumor cell-intrinsic PD-1 activation drives therapeutic resistance in colorectal cancer cells abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 586.