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VHL loss reprograms the immune landscape to promote an inflammatory myeloid microenvironment in renal tumorigenesis

ABSTRACT: 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. Using Vhl wildtype (WT) and knockout (KO) in vivo murine kidney cancer models, we found that Vhl KO tumors were less proliferative and more infiltrated by immune cells. Tumor-associated macrophages (TAM) demonstrated enhanced proinflammatory transcriptional signatures from Vhl deficient tumors, and intratumoral myeloid cells residing in the Vhl KO TME showed increased in vivo glucose consumption. Vhl loss did not confer increased in vivo glucose uptake in cancer cells or lymphocytes, or detectable changes in metabolites in the interstitial fluid. Mechanistically, 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. Here, we identify the importance of cancer cell-specific genetic features to drive environmental reprograming and shape the tumor immune landscape and identify a potential therapeutic target in the treatment of ccRCC.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE239889 | GEO | 2024/04/17

REPOSITORIES: GEO

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Project description:Altered metabolism is an important part of malignant transformation of tumor cells. Oncogenic transformation may reprogram tumor metabolism and render tumor cells addicted to extracellular nutrients. Such nutrient addictions associated with oncogenic mutations may offer therapeutic opportunities; however, it remains difficult to predict these nutrient addictions. Here, we performed a nutrigenetic screen to determine the phenotypes of isogenic pairs of clear-cell renal cancer cells (ccRCC) with or without VHL upon the deprivation of individual amino acids. We identified that cystine deprivation triggered rapid programmed necrosis in VHL-deficient RCC, but not in their VHL-restored counterparts. Similar cystine addiction was also observed in VHL-deficient primary RCC tumors cells. Blockage of cystine uptake significantly delayed xenograft growth of ccRCC. Importantly, cystine deprivation triggered similar metabolic changes regardless of VHL status. Therefore, metabolic differences due to cystine deprivation are not different enough to readily explain the distinct fate of life vs. death in VHL-deficient and restored cell.. Instead, we found that increased levels of TNFÎ± associated with VHL loss in the VHL-deficient RCC force them to rely on intact RIPK1 to inhibit apoptosis. However, this pre-existing elevated TNFÎ± in the VHL-deficient ccRCC renders these cells susceptible to the necrosis signaling triggered by cystine deprivation. In addition, we identified that cystine-deprived necrosis in VHL-deficient RCC depends on reciprocal amplification of the Src-p38-Noxa signaling and TNFÎ±-RIP1/3-MLKL necrosis pathways that culminate in MLKL oligomerization and programmed necrosis. Together, our data reveal that the contextual cystine-addictions in VHL-deficient ccRCC is dependent on activating pre-existing oncogenic pathways to trigger programmed necrosis. RNA was extracted by RNAeasy kits (Qiagen) from the RCC4 Vec and VHL-reconstituted cells which were exposed to the control full DMEM or cystine deprived DMEM media for 6 hours (three replicates in each condition).

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VHL loss reprograms the immune landscape to promote an inflammatory myeloid microenvironment in renal tumorigenesis

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