Abstract PR002: Enhancing anti-tumor immunity through targeting DDR2 on cancer-associated fibroblasts in ovarian cancer

Abstract Introduction: Ovarian cancer (OvCa) is the sixth-leading cause of cancer-related deaths in women in the United States. Patients will eventually succumb to this disease despite initial response to targeted therapies. Thus, new strategies to treatment are needed. One treatment approach is to identify ways to activate the immune system through modulating cancer-associated fibroblast (CAF) activity. CAFs, which are a type of stromal cell found in the tumor microenvironment, promote tumorigenesis through numerous mechanisms, including suppression of an anti-tumor immune response. We have specifically identified expression of the receptor tyrosine kinase Discoidin Domain Receptor 2 (DDR2) on CAFs as promoting immunosuppression in OvCa. Methods: For in vivo experiments, we used the ID8-Trp53 -/- ; Brca2 -/- (ID8TB) and the Kras G12V ; Trp53 -/- ; Ccne1 OE ; Akt2 OE (KPCA) syngeneic OvCa models with wild-type (WT) or global Ddr2 knockout (KO) C57BL/6 mice. We performed NanoString RNA-sequencing and spectral flow cytometry for characterization of the tumor microenvironment. For in vitro experiments, we used OvCa patient-derived CAFs expressing control or DDR2-targeting shRNAs. We also used T cells isolated from peripheral blood mononuclear cells from patients. We performed immunoblots and flow cytometry to assess the effects of the DDR2+ CAF secretome on T cells. Results: Using the ID8TB and KPCA models, we showed that Ddr2 KO mice exhibit decreased tumor burden compared to WT mice. NanoString mRNA-sequencing showed that ID8TB tumors from Ddr2 KO mice are transcriptionally enriched for gene sets involved in regulating lymphocyte signaling and activating an immune response. Additionally, Ddr2 KO mice showed decreased expression of the immunosuppressive protein Arginase 1 (Arg1) compared to tumors from WT mice. Subsequent flow cytometry experiments showed that tumors from Ddr2 KO mice exhibit increased infiltration of immune cells and cytotoxic (CD8+) T cells and decreased T cell exhaustion compared to tumors from WT mice. Correspondingly, in vitro, we showed that depleting DDR2 in patient-derived CAFs decreases expression of ARG1. Furthermore, conditioned media (CM) from DDR2-depleted CAFs leads to increased proliferation of patient-derived T cells compared to CM from control CAFs. Conclusion: We show that inhibiting DDR2 expression in OvCa CAFs suppresses ovarian cancer tumorigenesis by promoting anti-tumor T cell activity. Our work provides a rationale for the development of DDR2 inhibitors and for further studying DDR2 inhibition as a strategy for activating an anti-tumor immune response. Citation Format: Jaidev Bapat, Favour A. Akinjiyan, Ramya Parameswaran, Manon Miller, Sofia Ruau, Wanda Gan, Leah Wormack, Kailea Wiese, Katherine C. Fuh. Enhancing anti-tumor immunity through targeting DDR2 on cancer-associated fibroblasts in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr PR002.