VHL Deficiency and the Tumor Microenvironment in Renal Cell Carcinoma

Abstract

Clear cell renal cell carcinoma (ccRCC) is characterized by dysregulated hypoxia signaling and a tumor microenvironment (TME) highly enriched in myeloid and lymphoid cells. Loss of the von Hippel Lindau (VHL) gene is a critical early event in ccRCC pathogenesis and promotes stabilization of hypoxia inducible factors (HIF). Whether VHL loss in cancer cells impacts immune cells in the TME remains unclear. Using Vhl wildtype (WT) and knockout (KO) in vivo murine kidney cancer models, we found that Vhl KO tumors were more infiltrated by immune cells. Tumor-associated macrophages (TAM) from Vhl deficient tumors demonstrated enhanced in vivo glucose consumption, phagocytosis, and inflammatory transcriptional signatures, while lymphocytes from Vhl KO tumors showed reduced activation and reduced response to anti-PD-1 therapy in vivo. The chemokine, CX3CL1, is highly expressed in human ccRCC tumors and was associated with Vhl deficiency. Deletion of Cx3cl1 in cancer cells decreased myeloid infiltration associated with Vhl loss to provide a mechanism by which Vhl loss may contribute to the altered immune landscape. Here, we identify cancer cell-specific genetic features that drive environmental reprograming and shape the tumor immune landscape with therapeutic implications for the treatment of ccRCC.