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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE201514 | GEO | 2023/01/19

REPOSITORIES: GEO

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Project description:Combining direct anti-tumor effects with targeting of tumor microenvironment is an attractive strategy that may lead to more effective therapies for advanced melanoma. Here, we tested whether association of TRAIL with co-targeting of MEK and PI3K/mTOR, or with MEK blockade, could have synergistic anti-melanoma activity mediated not only by induction of tumor cell death, but also by effects on the tumor microenvironment. Drug interaction analysis by the Chou-Talalay approach in a panel of 21 melanoma cell lines indicated that strong synergism could be achieved by association of the MEK1/2 inhibitor AZD6244, the PI3K/mTOR inhibitor NPV-BEZ235 and TRAIL, as well as by the AZD6244/TRAIL combination. Synergism was observed on most tumors including TRAIL- or inhibitor-resistant melanomas, irrespective of the BRAF, NRAS, p53 and PTEN status, and was explained by enhanced induction of caspase-dependent melanoma apoptosis. The AZD/BEZ/TRAIL and AZD/TRAIL combinatorial treatments induced strong modulation of key apoptosis regulators along the extrinsic and intrinsic cell death pathways, including c-FLIP down-regulation, caspase-8 cleavage, BIMs and BAXa upregulation, clusterin and Mcl-1 inhibition, enhanced mitochondrial depolarization, suppression of inhibitors of apoptosis c-IAP1, c-IAP2, XIAP and Apollon, and caspase 3/7 activation. In an in vivo model, the AZD6244/TRAIL combinatorial treatment induced highly significant growth inhibition of a TRAIL-resistant tumor associated not only with melanoma cell death, but even with suppression of pro-angiogenic molecules HIF1a, VEGFa, IL-8 and TGFb1, and with inhibition of tumor angiogenesis. These results provide a proof of principle supporting the rationale for combinatorial treatments with synergistic anti-melanoma activity based on direct and indirect anti-tumor effects. The human melanoma cell line Me13 was established in our laboratory from a surgical specimen. Cells were routinely maintained in RPMI medium 1640 (Lonza, Basel, Switzerland) supplemented with 10% FBS (Lonza) and 2 mM glutamine (Lonza). Cells were maintained at 37°C in a water-saturated atmosphere of 5% CO2 in air. 3x10^6 cells were seeded in 75 cm2 flasks; after 24 hours, cells were left untreated or treated with Selumetinib (Selleck Chemicals, Houston, TX) at 0.1 micromol/L, NVP-BEZ-235 (Selleck Chemicals, Houston, TX) at 0.1 micromol/L and sTRAIL (AdipoGen) at 25ng/ml as single drugs or in combination for 8 hours. Each treatment or combination was performed in triplicate. At the end of treatment, cells were collected and RNA extracted.

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

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