Autocrine Control of CD276 by SPARC in Liver Cancer and Its Contribution to Immune Escape and Resistance to Immunotherapy

Vollständiger Abstract

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ABSTRACT Hepatocellular carcinoma (HCC) frequently demonstrates resistance to immunotherapeutic interventions, a phenomenon largely linked to mechanisms of immune escape. Among the modulators of the tumor microenvironment, SPARC (Secreted Protein Acidic and Rich in Cysteine), a matricellular glycoprotein, has been associated with diverse oncogenic processes in multiple cancer types. However, the contribution of SPARC to immune regulation through CD276 signaling remains insufficiently characterized. To clarify this mechanism, we employed the murine Hepa1‐6 hepatoma cell line established from C57BL/6 mice. Functional studies were carried out by genetically altering the expression of SPARC and CD276, followed by comprehensive assessments including Western blot analysis, polymerase chain reaction, flow cytometry, and in vivo tumorigenicity assays. Overexpression of SPARC in HCC cells led to increased CD276 levels through activation of the p65/c‐Myc axis, which also promoted cancer cell stemness. This upregulation impaired the response to immune checkpoint blockade (ICB) therapy, as evidenced by reduced infiltration and activation of CD8 + T cells within the tumor microenvironment. Additionally, increased SPARC‐induced CD276 expression diminished T‐cell activation and proliferation, marked by decreased IFN‐γ production and reduced phosphorylation of ZAP70, a key T‐cell signaling molecule. Our findings underscore the critical role of SPARC in upregulating CD276 in HCC, which contributes to immune suppression and resistance to ICB therapy.