Background: Clear cell renal cell carcinoma (ccRCC) is an aggressive disease characterized by dysregulated hypoxia signaling, metabolic defects, and a complex tumor microenvironment (TME) highly enriched in lymphoid and myeloid immune cells. Loss of the oxygen sensing gene, von Hippel Lindau (VHL), is a critical early event in ccRCC pathogenesis and promotes stabilization of hypoxia inducible factors (HIF) that upregulate pro-growth signaling pathways, including angiogenesis and aerobic glycolysis. However, whether VHL loss in cancer cells impacts the composition, metabolism, or function of immune cells in the TME remains unclear.
Methods: To answer this question, we used immunocompetent murine models of kidney cancer, in which we manipulated the VHL axis in vitro, to explore the impacts on immune cell repertoire and function in vivo.
Results: We found that VHL KO tumors were less proliferative and more infiltrated by immune cells. Tumor-associated macrophages (TAM) from VHL deficient tumors demonstrated enhanced proinflammatory transcriptional signatures and increased in vivo glucose consumption. VHL loss did not confer increased in vivo glucose uptake in cancer cells or lymphocytes, and did not result in detectable changes in metabolites in the interstitial fluid. Enhanced secretion of the chemokine, CX3CL1, was observed in VHL KO cancer cells and its cognate receptor, Cx3cr1, was significantly elevated on myeloid cells residing in the TME of VHL deficient tumors. Human ccRCC tumors exhibit high expression of CX3CL1 and CX3CR1 as well as enhanced myeloid metabolism and proinflammatory properties.
Conclusions: Here, we identify the importance of cancer cell-specific genetic features to drive environmental reprograming and shape the tumor immune landscape that may be a putative therapeutic target in the treatment of ccRCC.
