Abstract 6402: The effects of cytotoxic chemotherapy on colorectal cancer immunogenicity

Abstract

Abstract Introduction: Immunotherapy based on PD1/PDL1 and/or CTLA4 blocking antibodies has shown efficacy in the molecular subgroup of colorectal cancers (CRCs) characterized by deficient mismatch repair (MMRd). This feature, present in only 4-5% of metastatic CRCs, causes a significant increase of tumor mutational burden (TMB) and tumor neoantigens, ultimately leading to immune rejection. On the other hand, for the majority of MMR proficient (MMRp) CRCs, cytotoxic chemotherapy ± targeted agents still constitute the mainstay of the treatment Interestingly, even though it is known that cytotoxic agents induce mutations, their immunogenic potential is still not fully understood. The aim of this work is to systematically investigate the immunogenicity of chemotherapy-induced mutations in CRC. Methods: We performed a two-step experiment: first, murine CRC models were exposed to chemotherapy agents in an immune-free context (priming phase) and then challenged in immune-deficient and -proficient contexts (editing phase). Chemotherapy agents included the commonly used cytotoxic drugs 5-fluorouracil (5FU), oxaliplatin, SN38 (the active metabolite of irinotecan), cisplatin, and temozolomide, used as single drugs or combinations, in a pulsatile schedule using weekly ‘cycles’ (2 days on/5 days off) in order to mimic drug exposure in clinical settings. Whole exome sequencing (WES) was performed at baseline, and after both the priming and the editing phases. Results and discussion: WES analysis showed that cisplatin-based treatment is associated with the highest increase in TMB and predicted neoantigens when compared to 5FU-based combinations. Multiple mutational processes contribute to the accumulation of mutations upon exposure to chemotherapy, as revealed by analysis of mutational signatures. A statistically significant growth delay and increased survival was reported for tumors primed with cisplatin/temozolomide and 5FU/Oxaliplatin/SN38 (FOLFOXIRI) combinations compared to unprimed tumors in immunocompetent but not in immunodeficient mice, suggesting the active involvement of the immune system in controlling tumor growth. Sequencing data of residual (escaped) tumors at the end of the editing phase revealed a preferential loss of mutations etiologically linked to chemotherapy in the immunocompetent models, pinpointing an active immune-editing of chemotherapy-induced mutations. Conclusions: Cisplatin/temozolomide and FOLFOXIRI treatment effectively prime murine CRC models for subsequent immune rejection. These results suggest that the anticancer effect of chemotherapy treatment may be in part mediated by the immune-editing of chemotherapy-induced mutant cancer subclones. Citation Format: Pietro Paolo Vitiello, Rosaria Chilà, Giuseppe Rospo, Gaia Grasso, Giovanni Crisafulli, Alice Bartolini, Vito Amodio, Federica Di Nicolantonio, Giovanni Germano, Alberto Bardelli. The effects of cytotoxic chemotherapy on colorectal cancer immunogenicity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6402.