Targeting the αvβ5 Integrin Modifies the TGF-β-Rich Tumor Microenvironment of Pancreatic Cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is notorious for its aggressive, therapy-resistant nature that is in part driven by the desmoplastic, hypo-perfused, and immunosuppressive tumor microenvironment (TME). Here, we demonstrated that the αv integrin- and neuropilin-1 (NRP-1)-dual targeting iRGD peptide reverses some of these TME features by inhibiting transforming growth factor-β (TGF-β) activation in the tumor, a process mediated by the αvβ5 integrin. In addition to PDAC epithelial cells and fibroblasts, regulatory T cells (Tregs) in PDAC tumors also expressed the αvβ5 integrin and NRP-1. The αvβ5+ Tregs potently inhibited T cell proliferation, and systemic iRGD therapy not only depleted αvβ5+ Tregs from PDAC tumors but also reduced their αvβ5- counterparts. Mechanistically, iRGD inhibited the activation of TGF-β mediated by the αvβ5-rich TME, thereby depriving Tregs of the cytokine essential for their development and maintenance. NRP-1-dependent tumor penetration was required for this effect because a traditional RGD peptide without an NRP-1-binding motif failed to inhibit TGF-β signaling or deplete Tregs in vivo. Treatment with iRGD induced a series of additional TME changes, such as improved vascular patency and perfusion, reduced stromal fibers, and increased CD8+ T cell entry into the core of the tumors. Combining iRGD with immune checkpoint blockade led to an enhanced anti-tumor effect. Together, these findings support targeting the αvβ5 integrin with affinity ligands such as iRGD as a potential approach to enhance immunotherapy efficacy against PDAC and other desmoplastic tumors with high TGF-β and αvβ5 expression.