Thrombospondin-1 induced programmed death-ligand 1-mediated immunosuppression by activating the STAT3 pathway in osteosarcoma.

Abstract

Thrombospondin‐1 (TSP1) is generally assumed to suppress the growth of osteosarcoma through inhibiting angiogenesis; however, it is unclear whether TSP1 could affect the antitumor immunity against osteosarcoma. We aimed to explore the immune‐related tumor‐promoting effects of TSP1 and decipher its underlying mechanism. First, we identified that TSP1 regulated programmed death‐ligand 1 (PD‐L1) expression, which was related to the CD8+ T cells anergy in osteosarcoma cells. The exact role of PD‐L1 in the immunosuppressive effect of TSP1 was then further confirmed by the addition of the PD‐L1 neutralizing Ab. With the addition of PD‐L1 neutralizing Abs during cocultivation, the inhibition of CD8+ T cells was abolished to a certain extent. Further mechanistic investigations showed that TSP1‐induced PD‐L1 upregulation was achieved by activation of the signal transducer and activator of transcription 3 (STAT3) pathway. In vivo experiments also indicated that TSP1 overexpression could promote the growth of primary lesions, whereas TSP1 knockdown effectively inhibits the growth of the primary lesion as well as lung metastasis by restoring the antitumor immunity. Thrombospondin‐1 knockdown combined with PD‐L1 neutralizing Ab achieved a more pronounced antitumor effect. Taken together, our study showed that TSP1 upregulates PD‐L1 by activating the STAT3 pathway and, therefore, impairs the antitumor immunity against osteosarcoma.