Abstract 131: PDAC tumor growth suppression by targeting the CD49b collagen receptor through modulating the CD8+ T cell infiltration

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) has a desmoplastic extracellular matrix enriched with collagen type I (COL1) and poor CD8+ tumor-infiltrating lymphocyte (TIL) infiltration. CD49b, a key collagen receptor, has been implicated in PDAC progression, but its role in immune exclusion remains unclear. Objective: This study investigates the functional role of CD49b in modulating anti-tumor immune responses and collagen architecture in PDAC, while exploring its therapeutic potential against PDAC. Methods: Collagen receptors expression in PDAC was analyzed using flow cytometry on treatment-naïve human PDAC samples, Western blotting on PDAC cell lines including KPC cell lines, immunofluorescence on both human and mouse specimens, and analysis of single-cell RNA sequencing (scRNA-seq) on KPC models and human PDAC sample databases. The ITGA2 (CD49b) receptor was knocked out in KPC and Pan02 cells using CRISPR-Cas9. Tumor growth was evaluated in immunocompetent and immunodeficient mouse models, with or without CD8+ T cell depletion. Tumor-infiltrating lymphocytes (TILs) were assessed using FACs, and downstream signaling pathways were analyzed using RNA sequencing and Western blotting. Collagen fiber alignment was evaluated using CT-FIRE. Functional experiments included FAK overexpression to rescue signaling in CD49b-knockout models. Additionally, the consequence of blocking CD49b in vivo was examined. Results: CD49b was selectively expressed in PDAC cancer cells in both mouse and human specimens. Loss of CD49b impaired tumor adhesion to collagen and significantly suppressed tumor growth in an immunocompetent model by increasing activated intratumoral CD8+ T cell infiltration. Experimental depletion of CD8+ T cells abrogated tumor suppression in CD49b-deficient tumors, demonstrating the importance of CD8+ T cells in the anti-tumor response. Regarding affected signaling pathways, CD49b loss disrupted focal adhesion kinase (FAK) and pFAK signaling, increased CXCL10 chemokine expression, and altered collagen fiber alignment, creating a microenvironment permissive to immune infiltration. A negative correlation between CD49b expression and CD8+ T cell infiltration was observed between the tumor core and edge. FAK overexpression restored tumor growth in CD49b-deficient tumors. Furthermore, vatelizumab, a CD49b-blocking antibody, effectively inhibited PDAC-collagen adhesion and reduced tumor growth in hCD49b-expressing KPC tumor. Conclusion: This study reveals CD49b as a potent mediator of immune exclusion and collagen remodeling in PDAC and highlights its role in modulating FAK signaling and collagen alignment. Targeting CD49b, such as with vatelizumab, represents a novel and promising approach to overcome immune resistance and improve therapeutic efficacy in PDAC. Citation Format: Ibrahim R. Eissa, Motaz Qadan, Sonia Cohen, Genevieve M. Boland, Tatyana Sharova, Kenneth K. Tanabe. PDAC tumor growth suppression by targeting the CD49b collagen receptor through modulating the CD8+ T cell infiltration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 131.