Experimental type 1 diabetes metabolically rejuvenates CD8 ⁺ T cells for improved control of tumor growth through an IGF1-IGF1R axis

Epidemiological studies suggest that patients with pre-existing type 1 diabetes (T1D) have a decreased risk of developing melanoma, prostate cancer, and breast cancer, although the underlying mechanism remains to be elucidated. In translational modelling, we observed that streptozotocin (STZ) induced T1D mice exhibited restricted melanoma and carcinoma (mammary, lung and colon) growth in association with extended overall survival. Tumor-infiltrating CD8 ⁺ T cells were found to be responsible for tumor growth restriction. Tumor infiltrating CD8 ⁺ T cells but not tumor cells themselves exhibited higher glycolytic and cytotoxic activities in T1D hosts. Such improved anti-tumor T cell function was linked to selective upregulated expression of insulin-like growth factor 1, insulin-like growth factor 1 receptor, and phospho-mTOR in CD8 ⁺ T cells in the TME. T1D patient derived CD8 ⁺ T cells displayed superior activation in vitro after tumor antigen stimulation vs. non-diabetic CD8 ⁺ T cells. Activation of T1D patient derived 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 represents a preferred endpoint to achieving more effective immunotherapy outcomes and improved cancer patient management.