PD-1 blockade delays tumor growth by inhibiting an intrinsic SHP2/Ras/MAPK signalling in thyroid cancer cells

Abstract Background The programmed cell death-1 (PD-1) receptor and its ligands PD-L1 PD-L2 are immune checkpoints that suppress anti-cancer immunity. Typically, cancer cells express the PD-Ls bind PD-1 on cells, inhibiting their activity. Recently, expression has also been found in cells. Here, we analysed functions of thyroid (TC). Methods was evaluated by immunohistochemistry human TC samples RT-PCR, western blot FACS lines. Proliferation migration culture were assessed BrdU incorporation Boyden chamber assays. Biochemical studies performed blot, immunoprecipitation, pull-down phosphatase tumorigenicity xenotransplants nude mice. Results Human specimens (47%), but not normal thyroids, displayed epithelial which significantly correlated with tumour stage lymph-node metastasis. constitutively expressed overexpression/stimulation promoted proliferation migration. Accordingly, genetic/pharmacologic inhibition caused opposite effects. Mechanistically, recruited SHP2 to plasma membrane potentiated enhanced Ras activation dephosphorylating inhibitory tyrosine 32, thus triggering MAPK cascade. SHP2, BRAF MEK necessary for PD-1-mediated biologic functions. decreased, while enforced facilitated, xenograft growth mice affecting proliferation. Conclusions circuit blockade TC, besides restoring immunity, could directly impair SHP2/Ras/MAPK signalling pathway.