Cimetidine improves the a-CTLA-4 efficacy in melanoma by suppressing tumor PD-L1 expression 2513

Abstract Description Melanoma is a highly aggressive skin cancer with a rapidly increasing global prevalence. Immune checkpoint inhibitors (ICIs), such as antibodies targeting PD-1 and CTLA-4, have markedly improved outcomes for melanoma patients. However, the effectiveness of ICIs is often constrained by primary and acquired resistance, as well as severe immune-related adverse events, especially in combination therapies. To address these limitations, new ICIs, including a-LAG-3, a-TIM-3, and a-TIGIT and combination approaches with targeted therapies are under investigation. Cimetidine (CIM), widely used as a histamine H2 receptor antagonist, has shown potential in regulating immune responses against infections and tumors. However, its effect on regulating immune checkpoint expression has not been investigated. This study demonstrates that CIM significantly inhibited PD-L1 expression in both mouse and human melanoma cell lines, especially in primary cells derived from melanoma patients. Notably, CIM also suppressed PD-L1 expression in non-small cell lung cancer and colon cancer cell lines. In mice bearing B16F10 melanoma tumors, the anti-tumor effects of CIM were comparable to those of a-PD-L1 and, importantly, CIM enhanced the efficacy of a-CTLA-4 therapy by increasing CD8+ T cell responses. Theses results suggest that CIM could reduce PD-L1 expression in tumors and be employed in combination with a-CTLA-4 to treat melanoma and other solid tumors. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)