Experimental high blood glucose metabolically rejuvenates CD8+ T cells for improved control of tumor growth through an IGF1-IGF1R axis

Abstract Epidemiologic studies suggest that patients with pre-existing type 1 diabetes have a decreased risk of developing melanoma, prostate cancer, and breast cancer, although the underlying mechanism remains unresolved. In translational model studies, we observed that a streptozotocin-induced high blood glucose model exhibited restricted melanoma and carcinoma (mammary, lung, and colon) growth in association with extended overall survival. Tumor-infiltrating CD8+ T cells were responsible for tumor growth restriction. Tumor-infiltrating CD8+ T cells but not tumor cells themselves exhibited higher glycolytic and cytotoxic activity in high-glucose hosts. Such improved antitumor T cell function was linked to upregulated expression of Igf1, Igf1R, and phospho-mTOR in CD8+ T cells in the tumor microenvironment. High blood glucose patient-derived peripheral CD8+ T cells displayed superior activation in vitro after allogenic tumor antigen stimulation versus nondiabetic CD8+ T cells. Activation of high-glucose-patient CD8+ T cells was sensitive to targeted antagonism of IGF1R and mTOR, supporting the operational involvement of the IGF1R-mTOR signaling axis. Our results suggest that selective activation of the intrinsic IGF1R-mTOR signaling axis in CD8+ T cells serves as a preferred endpoint to achieving more effective immunotherapy outcomes in cancer patients.