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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.
Vitiello et al. (Thu,) studied this question.