TSC2 regulates tumor susceptibility to TRAIL-mediated T cell killing by orchestrating mTOR signaling

Resistance to immunotherapy continues to impair common clinical benefit. Here, we uncover an important role for Tuberous Sclerosis 2 (TSC2) in tumor susceptibility to killing by cytotoxic T lymphocytes, both in in vitro and in vivo. TSC2-depleted tumor cells show disruption of mTOR regulation upon CTL attack, which was associated by enhanced cell death responses. Mechanistically, we observed induced TRAIL receptor expression in TSC2-depleted cells, causing enhanced TRAIL sensitivity of tumor cells. Corroborating these data clinically, a negative correlation between TSC2 expression and TRAIL signaling was found in TCGA patient cohorts. Moreover, a lower TSC2 immune response signature was observed in melanoma patients responding to immune checkpoint blockade. Our study reveals a critical role for TSC2 in cancer immune response by crosstalk between TSC2-mTOR and TRAIL signaling, and merits therapeutic exploration of this pathway for immuno-oncology. Overall design: Human melanoma and lung cancer cell lines (Control or with TSC2 knock-out) were cultured in the presence of T cells or TRAIL overnight. Pure tumor cell populations were sorted for sequencing.