213P - Type-1 diabetes restricts melanoma growth by reprogramming intra-tumoral T cell metabolism

Background

Epidemiological studies from Bendix et al. (2016) with 5 countries and 9000 type-I diabetes mellitus (T1DM) patients with cancers showed reduced risk in melanoma, breast and prostate cancer and increased risk of oesophagus, stomach, colon and liver cancer, suggested differential consequences of T1DM with cancers of different etiopathology. However, prospective studies to decipher the possible mechanism are not well documented. In both T1DM and cancer, CD8⁺ T cells plays crucial role and faces functional as well as metabolic alterations. Objective of this study was to evaluate the possible modulatory effect of pre-existing T1DM in melanoma growth, systemic immune landscape and T cell metabolism.

Methods

Murine T1DM model was established by using intra-peritoneal injection of streptozotocin (STZ) to C57BL/6J mice. B16F10 cells were inoculated to T1DM and non-diabetic control mice. Tumor progression and host survival was closely monitored following establishment of B16 melanoma. RT-PCR, Western-blot, Flow-cytometry and LDH release assay were used to study different immune cells, metabolic pathways etc. Athymic nude mice were used to examine the possible involvement of immune system in T1DM associated cancer progression.

Results

Pre-existence of T1DM showed restricted melanoma growth and survival benefits in murine host, however, such effect was found to be mitigated in immune-compromised mice. Significant intra-tumoral infiltration of IFNg⁺Perforin^highGranzymeB^high CD8⁺ T cells were observed with reduced Tregs and MDSCs in T1DM host compared to control. Moreover, pre-existence of T1DM modulates extracellular acidification rate (ECAR) and expression of enzymes associated with glucose-metabolism like PCX1, LDH, PKM2 in tumor infiltrated CD8⁺T cells. Obtained results also pointed out the involvement of IGF1-mTOR signalling axis within CD8⁺-effector T cells in regulation of T1DM associated tumor growth restriction.

Conclusions

Pre-existing T1DM promotes CD8⁺ T cell dependent murine melanoma growth restriction which significantly increases tumor host survival. IGF1-mTOR signalling axis could be exploited in cancer patients with or without T1DM for therapeutic benefit.

Legal entity responsible for the study

R. Baral.

Funding

University Grants Commission, New Delhi, India. Indian Council of Medical Research, New Delhi, India.

Disclosure

All authors have declared no conflicts of interest.