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.
Keywords: 6TG; immune checkpoint inhibitors; immunotherapy; thiopurine; tumor mutational burden.