Abstract
Background: Decorin (DCN) predominantly produced by fibroblasts is a small leucine-rich proteoglycan with tumor-suppressive property. However, whether DCN has a role in shaping the tumor immune microenvironment remains elusive. Methods: The TCGA and GEO databases were analyzed to identify fibroblast-specific secretory proteins that are downregulated in most types of human tumors, positively correlate with CD8⁺ T cell infiltration, and associate with improved response to immune checkpoint blockade (ICB) therapy. The function of DCN in vivo was assessed using cell lines with stable DCN overexpression in both immunocompetent and immunodeficient mice. The changes in the composition and function of immune cell subpopulations in tumors were analyzed by flow cytometry analysis (FCM) and immunofluorescence staining. The role of CD8⁺ T cells in the DCN-mediated tumor suppression was further elucidated by utilizing B2m-knockout tumor cells and CD8⁺ T cell depletion assays. The in vitro co-culture system of tumor cells and T cells was applied to dissect the effects of DCN on CD8+ T lymphocyte activation and functions. Finally, the therapeutic efficacy of DCN in combination with anti-PD1 antibody was evaluated in mouse tumor model. Results: DCN-mediated tumor suppression was present in immunocompetent mice, wherein either depletion of CD8⁺ T cells in mice or ablation of β2M in tumor cells abrogated the tumor-inhibitory effects mediated by DCN, indicating the importance of CD8⁺ T cells in the DCN-antitumor activities. DCN overexpression promoted CD8⁺ T cell infiltration into tumors and increased the production of TNF-α, IFN-γ, and perforin in infiltrating T cells, and DCN expression substantially enhanced the tumor-suppressive efficacy of anti-PD1 therapy. More importantly, integrative analyses of clinical data indicated that DCN expression is downregulated in multiple types of human tumors and positively associated with the presence of CD8⁺ T cells and their expression of cytotoxic genes. Furthermore, high DCN levels were correlated with favorable prognosis in certain types of cancer patients with ICB therapy. Conclusions: Our study reveals that DCN functions as a tumor-suppressive factor by enhancing T cell response, and proposes the potential of exogenous DCN as a supplement to cancer immunotherapy.