Cancer cells impede T cell early activation and drive immune evasion by transferring Tmem176b

Despite its remarkable clinical success in human cancer treatment, immune checkpoint blockade is effective only in a minority of patients. One major obstacle is tumor-driven impairment of T cell priming and early activation, however, the underlying mechanism remains elusive. Here we identify TMEM176B-positive exosomes specifically secreted by cancer cells in plasma of cancer patients rather than healthy donors, high levels of which correlate with worse prognosis and unfavorable outcomes of anti-PD1 therapy. A small-scale CRISPR-Cas9 screen discovers Tmem176b on tumor-derived exosomes as a negative regulator of T cell early activation. Genetic ablation of Tmem176b in mouse cancer cells substantially suppresses tumour growth in a CD8 ⁺ T cell-dependent manner. Mechanistically, tumour-derived exosomal Tmem176b attenuates proximal T cell receptor signaling in CD8 ⁺ T cells by recruiting tyrosine phosphatase Shp1 to immunological synapse. Blocking TMEM176B, either using neutralizing antibody or using competitive peptide to disrupt Tmem176b-Shp1 interaction, remarkably restrains tumour progression in models of mouse and human cancers, and synergizes with anti-PD1/PD-L1 therapy. Our findings not only uncover tumor-derived Tmem176b as a promising target for cancer immunotherapy, but also provide a potential non-invasive diagnostic tool to detect early cancer and predict clinical response to anti-PD1 therapy.