Abstract IA019: Metabolic adaptations in renal cell carcinoma

Abstract

Abstract Clear cell renal cell carcinoma (ccRCC) is characterized by deregulated hypoxic signaling, metabolic defects, and a complex tumor microenvironment (TME) highly enriched in both lymphoid and myeloid immune subsets. Loss of the oxygen sensing gene, von Hippel Lindau (VHL), is a critical early event in ccRCC pathogenesis and promotes stabilization of hypoxia inducible (transcription) factors (HIF) that upregulate pro-growth signaling pathways, including angiogenesis and aerobic glycolysis. However, whether Vhl loss in cancer cells impacts the frequency, energetic requirements, or other functional properties of immune subsets in the TME remains unclear. Here, using Vhl WT and Vhl KO in vivo murine kidney cancer models, we found that Vhl KO tumors across multiple clones were slower growing and promoted increased immune cell infiltration in the TME. Enhanced proinflammatory signatures in tumor associated macrophage (TAM) subsets from Vhl deficient tumors were also observed, and these features were rescued when Vhl was reintroduced to the cancer cells. Moreover, in vivo quantification of the PET tracer and glucose analog, [18F]fluorodeoxyglucose (FDG), revealed that both myeloid derived suppressor cells (MDSC) and TAM populations from Vhl KO tumors consume more glucose than myeloid subsets from Vhl intact tumors. Notably, Vhl loss did not confer increased glucose uptake in cancer cells or lymphoid subsets in vivo. Overall, these data are consistent with enhanced metabolism and proinflammatory properties observed in the myeloid compartment of human ccRCC and highlight cancer cell intrinsic mechanisms driving environmental reprograming as a means of shaping the immune landscape in ccRCC. Citation Format: W. Kimryn Rathmell. Metabolic adaptations in renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr IA019.