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

  

Authors:	Vitiello, P. P.; Rousseau, B.; Chilà, R.; Battuello, P.; Amodio, V.; Battaglieri, V.; Grasso, G.; Scardellato, S.; Anselmo, A.; Clemente, F.; Rospo, G.; Lamba, S.; Bartolini, A.; Pisati, F.; Tripodo, C.; Congiusta, N.; Russo, M.; Crisafulli, G.; Di Nicolantonio, F.; Germano, G.; Diaz, L. A. Jr; Bardelli, A.
Article Title:	Cisplatin and temozolomide combinatorial treatment triggers hypermutability and immune surveillance in experimental cancer models
Abstract:	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. © 2025 The Author(s)
Keywords:	cisplatin; chemotherapy; temozolomide; colorectal cancer; immune surveillance; cytotoxic chemotherapy; immune checkpoint blockade; neoantigens; immune rewiring; mismatch repair modulation
Journal Title:	Cancer Cell
ISSN:	1535-6108
Publisher:	Cell Press
Publication status:	Online ahead of print
Date Published:	2025-06-12
Online Publication Date:	2025-06-12
Language:	English
DOI:	10.1016/j.ccell.2025.05.014
PROVIDER:	scopus
PUBMED:	40513578
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-105008136838&doi=10.1016%2fj.ccell.2025.05.014&partnerID=40&md5=9f8a0e4edab6cb970980568d654aa8d6
Notes:	Article -- MSK corresponding author is Luis Diaz Jr -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/226374