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Targeting USP8 inhibits Cancer Progression and Prevents EV-TβRII-Induced Exhaustion of CD8+ T cells

ABSTRACT: TGF-β signalling is a key player in tumor progression, immune evasion, and poor response to cancer immunotherapies. Here, we identified USP8 as a metastasis enhancer and a highly active deubiquitinase in aggressive breast tumors. USP8 acts as a cancer stemness-promoting factor that also mediates the activation of the TGF-β/SMAD signalling pathway. USP8 directly deubiquitinates and stabilises TβRII, increasing its expression in the plasma membrane and in tumor-derived extracellular vesicles (TEVs). Frequent gain of USP8 function was observed in patients resistant to neoadjuvant chemotherapies. USP8 promotes TGF-β/SMAD-induced epithelial to mesenchymal transition (EMT), invasion, and metastasis in tumor cells, and meanwhile, USP8 enables the TβRII+ circulating extracellular vesicles (crEVs) induce T-cell-exhaustion and chemoimmunotherapy resistance. Pharmacological inhibition of USP8 antagonises TGF-β/SMAD signalling and effectively reduces TβRII stability and the number of TβRII+ crEVs, thereby preventing CD8+ T cell exhaustion and reactivating anti-tumor immunity. Our findings not only identified a novel mechanism whereby USP8 regulates the cancer microenvironment, but also demonstrated the therapeutic advantages of engineering USP8 inhibitors to simultaneously suppress metastasis and improve the efficacy of cancer immunotherapy.

SUBMITTER: Feng Xie

PROVIDER: S-SCDT-EMBOJ-2021-108791 | biostudies-other |

REPOSITORIES: biostudies-other

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