Tenascin-C shapes TRAIL control over tumor immunity

ABSTRACT: TRAIL cytotoxicity is exploited as anti-cancer therapy since many years, however incomplete knowledge is generating many obstacles. Here, we address whether the highly abundant extracellular matrix molecule tenascin-C (TNC) orchestrating an immune suppressive tumor microenvironment and binding TRAIL impacts TRAIL cytotoxicity. We used an immune competent autologous NT193 breast cancer model with a knockdown (KD) of Tnfsf10 (encoding TRAIL) and observed accelerated tumor growth marked by less apoptosis, more proliferation and less myeloid cell infiltration as seen by flow cytometry. Grafting the same Tnfsf10 KD cells into a TNC knockout host showed repressed tumor growth suggesting that TNC is involved in regulating TRAIL functions. In vitro, we saw reduced macrophage invasion and phagocytosis with conditioned medium from Tnfsf10 KD tumor cells proposing a role of TRAIL in counteracting tumor growth. We further demonstrated that TRAIL increases secretion of TGF2/3 inducing CXCR4 in macrophages. Here, we have discovered regulation of TRAIL cytotoxicity through cell plasticity orchestrated by TNC. The pro-tumorigenic effects of TNC, counteracting TRAIL cytotoxicity, entail repression of Tnfsf10 through integrin and, abolishing TRAIL-receptor DR5 and E-cadherin expression. As the MAREMO peptide MP5 inhibits TNC actions, we determined whether targeting TNC with MP5 has an impact on TRAIL cytotoxicity. Indeed, MP5 enforces an epithelial phenotype and elevates DR5 expression thus causing sensitization to TRAIL-induced cell death. Moreover, MP5 inhibited tumor growth that was less pronounced in Tnfsf10 KD tumors suggesting MP5 to empower endogenous TRAIL cytotoxicity. Kaplan-Meier analysis demonstrated that a high TRAIL expression correlates with favorable breast and gastric cancer patient survival which is abolished when TNC levels are also high. Our results predict that tumors with lower TNC might be more responsive to therapeutic TRAIL cytotoxicity and that MP5 could be a novel tool for enhancing TRAIL therapy.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

SUBMITTER: Aurélie Hirschler  

LAB HEAD: Christine Carapito

PROVIDER: PXD045388 | Pride | 2026-04-15

REPOSITORIES: Pride