Thiopurine therapy enhances immune checkpoint inhibitor efficacy in low-mutational burden melanoma: A promising anticancer approach.

Abstract

A key limitation of immune checkpoint inhibitors (ICI) therapy is their reduced efficacy toward cancers with a low tumor mutational burden (TMB). Since low-TMB tumors express fewer neoantigens, they are less responsive to ICI therapy like anti-PD-1 and anti-CTLA-4. In preclinical immunocompetent mouse models of low-TMB melanoma, we recently demonstrated that exposure to 6-thioguanine (6TG) significantly improved tumor control by increasing TMB and creating a proinflammatory tumor microenvironment. The combination of 6TG with anti-PD-1 further improved tumor control, although it did not fully inhibit tumor growth. We here investigated additional ICI combinations, assessing anti-CTLA-4 with anti-PD-1 to improve efficacy. ICI eliminated tumors in 6TG-exposed mice when ICI treatment was initiated at tumor volumes of 20 mm³, stopped tumor growth at volumes of 120 mm³, and had no effect at volumes of 300 mm³. Finally, we showed that mice achieving complete tumor regression with 6TG and ICI treatment exhibited lasting immune memory, which effectively suppressed tumor growth at relapse upon re-exposure to tumor cells. These findings may pave the way to effective application of ICI to low-TMB cancers, when initiated at low tumor volume.