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Sulindac Modulates the Response of Proficient MMR Colorectal Cancer to Anti-PD-L1 Immunotherapy
Bin Yi1,2, Hao Cheng1,2, Dorota Wyczechowska2
1Department of Genetics, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
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.
Insights
This study shows sulindac enhances anti-PD-L1 immunotherapy for proficient mismatch repair (pMMR) colorectal cancer by reducing PD-L1 expression. Combination therapy significantly reduced tumor growth and increased T cell infiltration.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- Immune-checkpoint inhibitor (ICI) therapy is effective for some cancers, but benefits are limited in colorectal cancer (CRC) patients with proficient mismatch repair (pMMR).
- Current treatments offer minimal benefit for the majority of pMMR CRC patients, necessitating novel therapeutic strategies.
Purpose of the Study:
- To investigate the efficacy of sulindac in combination with anti-PD-L1 immunotherapy for pMMR colorectal cancer.
- To elucidate the underlying mechanisms by which sulindac enhances anti-PD-L1 therapy response.
Main Methods:
- Utilized a CT26 syngeneic mouse tumor model to assess tumor growth inhibition.
- Compared the effects of PD-L1 antibody (Ab), sulindac, and combination therapy.
- Analyzed tumor-infiltrating CD8+ T lymphocytes and PD-L1 expression pathways (NF-κB, exosomal PD-L1).
Main Results:
- Combination therapy significantly reduced tumor volume in pMMR colorectal cancer models.
- Enhanced infiltration of CD8+ T lymphocytes was observed in tumors treated with combination therapy.
- Sulindac downregulated PD-L1 by blocking NF-κB signaling, reducing exosomal PD-L1 and increasing anti-PD-L1 Ab availability.
Conclusions:
- Sulindac acts as an immunomodulatory agent, enhancing anti-PD-L1 therapy efficacy in pMMR colorectal cancer.
- The combination strategy shows promise for overcoming resistance to ICI therapy in this patient population.
- Low-dose sulindac did not systemically inhibit prostaglandin E2 (PGE2).
