Dr. National Institute of Pharmaceutical Education and Research Mohali S.A.S Nagar, Punjab, India
Introduction/Rationale: Epidemiological studies from Bendix et al. (2016) with 5 countries and 9000 T1DM patients suggest that patients with pre-existing T1DM have a decreased risk of developing melanoma, prostate, and breast cancer, although the underlying mechanism remains unresolved.
Methods: Murine T1DM model was established by using intra-peritoneal injection of streptozotocin (STZ) to C57BL/6J mice. B16F10 melanoma, Lewis lung carcinoma and CT26 colon carcinoma cells were inoculated to T1DM and non-diabetic control mice. Tumor progression and host survival was monitored. RT-PCR, Western-blot, Flow-cytometry, LDH release, and Seahorse assay were used to study different immune cells, metabolic pathways etc. Athymic nude mice were used to examine the possible involvement of immune system.
Results: Pre-existence of T1DM showed restricted tumor growth and survival benefits in murine host, and, such effect was mitigated in immune-compromised mice. Significant intra-tumoral infiltration of CD8+IGFR+IGF1+T cells with high IFN, Perforin and Granzyme B expression was observed in T1DM-tumor host compared to control. Moreover, pre-existence of T1DM modulates extracellular acidification rate and expression of enzymes associated with glucose-metabolism and mitochondrial metabolism in tumor infiltrated CD8+T cells. Obtained results pointed out the involvement of IGF1-mTOR signaling axis within CD8+ effector T cells in regulation of T1DM associated improved mitochondrial metabolism and tumor growth restriction. Moreover, T1DM patient derived peripheral CD8+ T-cells displayed superior activation in vitro after tumor antigen stimulation vs. non-diabetic CD8+ T-cells. Activation of T1DM patient CD8+T-cells was sensitive to targeted antagonism of IGF1R and mTOR.
Conclusion: Our results suggest that selective activation of the intrinsic IGF1R-mTOR signaling axis in CD8+T-cells serves as a preferred endpoint to achieve more effective immunotherapy outcomes in cancer
