Caloric Restriction Ameliorates Aging and Tumor Progression Via Tumor Immunity in Syngeneic Mice Model

Caloric restriction (CR) without malnutrition reportedly improves life span and ameliorates aging in preclinical models. Decreased expressions of aging-related genes and inflammation-related genes have been observed in CR mice. Moreover, CR decreases cancer risk and inhibits tumor progression, but the underlying mechanisms are not fully understood. In this study, we developed a syngeneic model using C57BL/6N male mice, and verified the tumor-suppressing mechanisms of CR. Mice were randomized into 2 groups: normal diet (ND) group fed with ad lib diet, and CR group with 30% reduced feeding compared with the ND group, started from 2 months age. MC38, murine colorectal adenocarcinoma cells, were implanted subcutaneously. We compared tumor growth and survival between the CR group and the ND group. Moreover, to verify the contribution of tumor immunity, we compared the tumor-suppressing effects of anti-PD-1 antibody between the CR group and the ND group. To clarify the impacts of CD8+ cytotoxic T cells, we also conducted CD8 depletion by anti-CD8 antibody. Firstly, we observed significantly restricted tumor progression of the CR group in aged mice, but it was relatively modest in young mice. Secondly, the tumor-suppressing effect of anti-PD-1 was equivalent between the CR group and the ND group in aged mice, which suggests tumor immunity is essential to demonstrate anti-tumor effects in CR mice. However, CD8 depletion in CR mice showed only partial tumor-promoting effects, which suggests immune function excluding CD8+ T cells contributes to suppressing tumor progression in the CR group. Our findings suggest that CR ameliorates aging and tumor progression. Promoted immune function, especially immune cells excluding CD8+ T cells, might play a role in the tumor-suppressing effects of CR. CD4 depletion and comprehensive analyses of intratumoral T cells are currently underway to elucidate the underlying mechanisms of tumor suppression induced by CR. Taichi Horino, Haruki Horiguchi, Yuji Miyamoto, Masaaki Iwatsuki, Yuichi Oike. Caloric restriction ameliorates aging and tumor progression via tumor immunity in syngeneic mice model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2554.