Abstract
Background: Immune checkpoint inhibitors have been approved for first-line treatment of metastatic clear cell renal cell carcinoma (ccRCC), but limited therapeutic effects have been reported in patients with advanced ccRCC. Investigating vital targets in specific immune interactions and their effect on the tumor microenvironment of ccRCC could provide novel strategies for overcoming the above limitations. Methods: We investigated the expression characteristics, prognostic role, and immune associations of OAS3 in the tumor microenvironment in patients with ccRCC. The functions of OAS3 in proliferation and migration were explored in 786-O and OS-RC-2 cells by forced OAS3 overexpression or knockdown. Furthermore, a xenograft model was established in C57BL/6 mice to study the combined effects of OAS3 downregulation and anti-PD1 therapy. The growth, proliferation, and apoptosis of tumor cells, as well as the infiltration of CD8+ T cells and M1/M2 macrophages within tumor tissues, were evaluated by immunohistochemistry. Results: OAS3 was upregulated in ccRCC and significantly associated with the overall survival of patients with ccRCC. OAS3 expression levels were correlated with genomic mutation profiles and were positively associated with the infiltration of CD8+ T cells, macrophages, neutrophils, and dendritic cells. OAS3 upregulation increased the proliferation, migration, invasion, and colony formation abilities of 786-O and OS-RC-2 cells. In contrast, OAS3 knockdown had the opposite effect. In vivo experiments revealed that OAS3 downregulation repressed the growth and proliferation of tumor cells, and promoted infiltration of M2 macrophages but enhanced the apoptosis and infiltration of CD8+ T cells. The phosphorylation of NF-κB p65 was repressed by OAS3 downregulation. In addition, the combination of anti-PD1 therapy and OAS3 downregulation had synergistic antitumor effects. Conclusion: OAS3 is upregulated in ccRCC and promotes tumor progression by mediating the infiltration of immune cells in the TME. OAS3 represents a promising therapeutic target for enhancing the antitumor effects of immune checkpoint inhibitors.