Experimental high blood glucose metabolically rejuvenates CD8+ T cells for improved control of tumor growth through an IGF1-IGF1R axis
Anirban Sarkar, Sukanya Dhar, Saurav Bera, Mohona Chakravarti, Ayushi Verma, Muqtada Ali Khan, Parash Prasad, Anupam Das, Pritha Roy Choudhury, Jasmine Sultana, Juhina Das, Akata Saha, Avishek Bhuniya, Ipsita Guha, Shayani Dasgupta, Sib Sankar Roy, Saptak Banerjee, Subir Roy, Debarati Bhar, Walter J Storkus, Rathindranath Baral, Dipak Datta, Anamika BoseAbstract
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.