HSP47 Destabilizes CD155 Through TRAF2 in Synergistic Anti-TIGIT Treatment of Osteosarcoma

Abstract

Abstract Heat shock protein 47 (HSP47) plays an essential role in correcting protein folding, and abnormal protein folding is closely related to tumorigenesis. However, the relationship between HSP47 and cancer immune response is poorly studied. Herein, HSP47 was found to be frequently overexpressed in human osteosarcomas. In animal models, HSP47 inhibition resulted in enhanced immune cell infiltration and function. Transcriptome data revealed that HSP47 negatively regulated CD155, a ligand of TIGIT. Immune checkpoint blockade therapy targeting the novel immune checkpoint molecule TIGIT is effective in limited patients. Further investigations are urgently needed to harness a robust response of this treatment. TIGIT antibody and HSP47-targeted therapy significantly inhibited the progression of osteosarcoma in mice and consequently prolonged survival. Mechanistically, inhibition of HSP47 attenuated TRAF2 protein ubiquitination and subsequently facilitated NF-κB-mediated CD155 transcription in HSP47-overexpressed osteosarcomas. Similarly, CD155 expression was significantly weakened in TRAF2-inhibited osteosarcoma cells. Collectively, our data revealed that targeting HSP47 could reinforce the expression of CD155 and therefore enhance the efficacy of anti-TIGIT treatment, providing a promising strategy for cancer immunotherapy.