Sulindac Modulates the Response of Proficient MMR Colorectal Cancer to Anti–PD-L1 Immunotherapy

Abstract Immune-checkpoint inhibitor (ICI) therapy has been widely used to treat different human cancers, particularly advanced solid tumors. However, clinical studies have reported that ICI immunotherapy benefits only ∼15% of patients with colorectal cancer, specifically those with tumors characterized by microsatellite instability (MSI), a molecular marker of defective DNA mismatch repair (dMMR). For the majority of patients with colorectal cancer who carry proficient MMR (pMMR), ICIs have shown little clinical benefit. In this study, we examined the efficacy of sulindac to enhance the response of pMMR colorectal cancer to anti–PD-L1 immunotherapy. We utilized a CT26 syngeneic mouse tumor model to compare the inhibitory effects of PD-L1 antibody (Ab), sulindac, and their combination on pMMR colorectal cancer tumor growth. We found that mice treated with combination therapy showed a significant reduction in tumor volume, along with increased infiltration of CD8+ T lymphocytes in the tumor tissues. We also demonstrated that sulindac could downregulate PD-L1 by blocking NF-κB signaling, which in turn led to a decrease in exosomal PD-L1. Notably, PD-L1 Ab can be bound and consumed by exosomal PD-L1 in the blood circulation. Therefore, in combination therapy, sulindac downregulating PD-L1 leads to increased availability of PD-L1 Ab, which potentially improves the overall efficacy of anti–PD-L1 therapy. We also show that low-dose sulindac does not appear to have a systemic inhibitory effect on prostaglandin E2 (PGE2). In conclusion, our findings provide unique insights into the mechanism of action and efficacy for sulindac as an immunomodulatory agent in combination with anti–PD-L1 therapy for the treatment of pMMR colorectal cancer.