Abstract A007: Endothelial cell-mediated immune suppressive mechanism in ccRCC and the implication for effective immune check point therapy

Abstract Clear-cell renal cell carcinoma (ccRCC) is the most common and aggressive subtype of renal cancer, accounting for over 80% of cases. Conventional chemotherapies show limited efficacy and targeted receptor tyrosine kinase inhibitor (RTKi) therapy often induces drug resistance, and tends to become ineffective when the leaky vasculature is repaired by the RTKi treatment. The advent of immune checkpoint inhibitors (ICIs) has therefore become a critical component of ccRCC management. However, the response rate is still disappointing at ∼30%. Here we uncover an endothelial cell (EC)-mediated immune suppressive mechanism induced by the Oncostatin M signaling emanated from the ccRCC tumor cells. The ccRCC-associated ECs exhibit distinct immune suppressive signature, expressing, e.g., CD200 and Amyloid Beta Precursor Protein (APP) that drive the formation of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Treg's), which express CD200R and CD274. These suppressor cells are formed in the vasculature before anti-tumor immune cells can reach the tumor proper, thus forming an effective barrier of immune checkpoint. Therefore if PD-L1 expression in tumor cells is the diagnostic criteria for choosing ICI therapy based on anti-PDL1/anti-PD-1, a large population of ccRCC patients with CD200 expression in ECs would be disadvantaged. Significantly, inactivating CD200 in the VHL conditional KO (Hoxb7-Cre-GFP; Vhlh loxP/loxP ) background rescues the premalignant phenotypes such as hyperplasia, infiltration of immune cells, and cyst formation of the autochthonous ccRCC model. We also devise a syngeneic mouse ccRCC model by inactivating the VHL gene in the mouse RENCA RCC tumor cells. This cell line is then xenografted orthotopically in immune-competent BALB/c mouse. The resulting tumor is aggressive and shows typical clear-cell phenotypes. Anti-CD200 treatment shows effective anti-tumor effects in single therapy and the efficacy is further enhanced in combination with anti-PD-1 therapy. Importantly, since CD200 is specifically expressed by the tumor-associated ECs, the therapy can be targeted against the ECs with minimal side effects, and does not rely on the leaky tumor vasculature for targeting the tumor cells. Citation Format: Hieu-Huy Nguyen-Tran, Thi-Ngoc Nguyen, Tien Hsu. Endothelial cell-mediated immune suppressive mechanism in ccRCC and the implication for effective immune check point therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr A007.