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

IF 48.8 1区医学 Q1 CELL BIOLOGY

Cancer Cell Pub Date : 2025-06-12 DOI:10.1016/j.ccell.2025.05.014

Pietro Paolo Vitiello, Benoit Rousseau, Rosaria Chilà, Paolo Battuello, Vito Amodio, Vittorio Battaglieri, Gaia Grasso, Sharon Scardellato, Achille Anselmo, Francesca Clemente, Giuseppe Rospo, Simona Lamba, Alice Bartolini, Federica Pisati, Claudio Tripodo, Noemi Congiusta, Mariangela Russo, Giovanni Crisafulli, Federica Di Nicolantonio, Giovanni Germano, Alberto Bardelli

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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.

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顺铂和替莫唑胺联合治疗在实验癌症模型中引发超易变性和免疫监视

错配修复（MMR）失活诱导的超突变导致结直肠癌（CRC）和其他几种恶性肿瘤的免疫监视。我们研究了合理设计的化疗组合对免疫难治性CRC和乳腺癌小鼠模型中高突变和免疫原性产生的影响。顺铂（CDDP）和替莫唑胺（TMZ）联合治疗可诱导MMR的适应性下调，导致化疗依赖性高易变性和预测新抗原的增加。这种组合特异性地改变肿瘤的免疫适应性，最终导致CD8+ T细胞介导的免疫监视，化疗诱导的新抗原的免疫编辑和持久的免疫记忆。CDDP和TMZ治疗还可以重塑小鼠的先天免疫微环境，并在与抗pd -1治疗联合时诱导持久反应和完全排斥。临床批准的5-氟尿嘧啶、奥沙利铂和伊立替康联合使用（FOLFOXIRI）没有观察到同样的效果。治疗诱导的超突变可以增强抗肿瘤免疫反应，为癌症治疗提供了额外的途径。

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来源期刊

Cancer Cell 医学-肿瘤学

CiteScore

55.20

自引率

1.20%

发文量

179

审稿时长

4-8 weeks

期刊介绍： Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.