Abstract A038: Antigen Presentation By Cancer-Associated Fibroblasts

Abstract Introduction: Immunotherapy has shown promise in treating some patients with metastatic diseases, but the effectiveness of the immune system in controlling cancer is hampered by a suppressive tumor microenvironment (TME), in which cancer-associated fibroblasts (CAFs) play a key role. Developing new and highly specific immunotherapeutic tools targeting CAFs may have a significative impact on tumor control. For this purpose, we aim to investigate antigen presentation characteristics by MHC-I molecules in CAFs and identify targetable CAF-specific antigens. Methods and Results: Analysis of existing single-cell datasets revealed higher expression of MHC-I in CAFs compared to normal fibroblasts (p<0.05) in various tumor types. In melanoma, higher MHC-I expression was linked to resistance to immune checkpoint blockade (ICB). Additionally, we found a positive correlation between MHC-I expression and immunosuppressive molecules such as galectin-9 and HVEM. These observations were supported by initial flow cytometry analyses in CAF cell lines derived from patients. Furthermore, prolonged and severe hypoxia further elevated MHC-I protein levels in CAF cell lines. Using a proteogenomic approach with mass spectrometry, we identified over 10,000 antigens in five patient-derived CAF cell lines from primary breast cancer tumors and one normal fibroblast cell line. By integrating single-cell and bulk RNA sequencing data from various tumors and normal tissues, we identified more than 20 CAF-specific or fibroblast-specific antigens. Conclusion: CAFs exhibit high MHC-I expression, which is amplified under hypoxic conditions. We have identified CAF-specific antigens that require evaluation for their immunogenicity, indicating the potential of CAFs as targets for antigen-based therapies. Citation Format: Eralda Kina, Caroline Côté, Jean-David Larouche, Chantal Durette, Joel Lanoix, Eric Bonneil, Jean-Philippe Laverdure, Gabriel Ouellet Lavallée, Margaret Buchanan, Adriana , Fatima Mechta-Grigoriou, Pierre Thibault, Mark Basik, Claude Perreault. Antigen Presentation By Cancer-Associated Fibroblasts [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A038.