Cisplatin and temozolomide combinatorial treatment triggers hypermutability and immune surveillance in experimental cancer models

Hypermutation induced by mismatch repair (MMR) inactivation leads to immune surveillance in colorectal cancer (CRC) and in several other malignancies. We investigated the impact of a rationally designed chemotherapy combination on the generation of hypermutation and immunogenicity in otherwise immune-refractory CRC and breast cancer mouse models. Combinatorial treatment with cisplatin (CDDP) and temozolomide (TMZ) induces an adaptive downregulation of MMR, resulting in chemotherapy-dependent hypermutability and increase in predicted neoantigens. This combination specifically alters the immune fitness of the tumors, ultimately leading to CD8 + T cell-mediated immune surveillance, immunoediting of chemotherapy-induced neoantigens, and durable immunological memory. Treatment with CDDP and TMZ also remodels the innate immune microenvironment and induces long-lasting responses and complete rejections when combined with anti-PD-1 therapy in mice. The same effects are not observed using the clinically approved combination of 5-fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI). Treatment-induced hypermutation can enhance anti-tumor immune responses, offering additional avenues for cancer treatment. • CDDP-TMZ combination causes adaptive MMR downregulation and hypermutability • CDDP-TMZ-induced neoantigens elicit durable CD8 + T cell-mediated immune response • CDDP-TMZ treatment promotes an antitumor immune microenvironment • In vivo treatment with CDDP, TMZ, and anti-PD-1 results in enhanced therapeutic efficacy Vitiello et al. describe how the chemotherapy combination of cisplatin and temozolomide fosters anti-tumor immune surveillance by remodeling the immune microenvironment, inducing hypermutation, and generating novel neoantigens in otherwise immune-refractory mismatch repair (MMR)-proficient cancer models.