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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.

ORGANISM(S): Mus musculus

PROVIDER: GSE330526 | GEO | 2026/05/11

REPOSITORIES: GEO

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Project description:Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) dramatically limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that VS-4718 rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME thus rendering tumors more responsive to immunotherapy. We treated KP orthotopic tumor-bearing mice with vehicle and FAK inhibitor (FAKi) for 14 days, then extracted total RNA from tumor tissues.

Project description:Pancreatic ductal adenocarcinoma (PDAC) is considered an immunologically cold cancer type. This perception is due to its rapid progression, strong presence of immunosuppressive cells and lack of response to current immunotherapies. However, we and others have shown that many patient PDAC tumors contain robust lymphocyte infiltration, aggregated in the form of tertiary lymphoid structures (TLS). The presence of TLS in PDAC is prognostic for long-term survival and in other cancer types, predictive of response to immunotherapy. Despite the clinical benefit to generating TLS in tumors, why they form in some PDAC patients but not others, remains unknown. The desmoplastic stroma in PDAC contributes to defective anti-tumor immunity largely due to myofibroblastic cancer associated fibroblasts (myCAF) induced by transforming growth factor-beta (TGF). Other groups have demonstrated that mesenchymal cell phenotypes with lymphoid tissue organizing properties regulate TLS formation in tumors. In order to restore effective anti-tumor immunity for PDAC patients, CAF phenotypes must be reprogrammed to support rather than restrict intratumoral immune activity. Using a lymphotoxin beta receptor (LTBR) agonist we observed induction of TLS-like aggregates in some murine PDAC tumor models, but not others. The CAF phenotypes of TLS-resistant models were predominantly myCAF while the TLS-permissive models were enriched for a VCAM1+ICAM1+ reticular-CAF (rCAF) subset. Induction of myCAF differentiation in vitro with TGF1 silenced LTBR/TNFR mediated upregulation of rCAF chemokine expression and attenuated B and T cell migration towards fibroblasts. Therapeutic TGFR1 inhibition ameliorated these effects thereby allowing LTBR agonism to repolarize rCAF phenotypic programming associated with improved lymphocyte recruitment and T cell-dependent tumor control. In patient PDAC tumors, rCAF resided next to TLS while myCAF were distally located. These data indicate that the myCAF-regulated PDAC stroma antagonizes acquisition of rCAF subsets critical for TLS formation but can be therapeutically remodeled to promote beneficial immune responses in immunosuppressive PDAC tumors.

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

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