VHL loss reprograms the immune landscape to promote an inflammatory myeloid microenvironment in renal tumorigenesis
Melissa M. Wolf, … , W. Kimryn Rathmell, Jeffrey C. Rathmell
Melissa M. Wolf, … , W. Kimryn Rathmell, Jeffrey C. Rathmell
Published April 15, 2024
Citation Information: J Clin Invest. 2024;134(8):e173934. https://doi.org/10.1172/JCI173934.
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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 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 HIF. Whether VHL loss in cancer cells affects immune cells in the TME remains unclear. Using Vhl WT and Vhl-KO in vivo murine kidney cancer Renca models, we found that Vhl-KO tumors were more infiltrated by immune cells. Tumor-associated macrophages (TAMs) from Vhl-deficient tumors demonstrated enhanced in vivo glucose consumption, phagocytosis, and inflammatory transcriptional signatures, whereas lymphocytes from Vhl-KO tumors showed reduced activation and a lower response to anti–programmed cell death 1 (anti–PD-1) therapy in vivo. The chemokine CX3CL1 was highly expressed in human ccRCC tumors and was associated with Vhl deficiency. Deletion of Cx3cl1 in cancer cells decreased myeloid cell infiltration associated with Vhl loss to provide a mechanism by which Vhl loss may have contributed to the altered immune landscape. Here, we identify cancer cell–specific genetic features that drove environmental reprogramming and shaped the tumor immune landscape, with therapeutic implications for the treatment of ccRCC.

Authors

Melissa M. Wolf, Matthew Z. Madden, Emily N. Arner, Jackie E. Bader, Xiang Ye, Logan Vlach, Megan L. Tigue, Madelyn D. Landis, Patrick B. Jonker, Zaid Hatem, KayLee K. Steiner, Dakim K. Gaines, Bradley I. Reinfeld, Emma S. Hathaway, Fuxue Xin, M. Noor Tantawy, Scott M. Haake, Eric Jonasch, Alexander Muir, Vivian L. Weiss, Kathryn E. Beckermann, W. Kimryn Rathmell, Jeffrey C. Rathmell

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Figure 2

Vhl loss functionally upregulates HIF targets in the Renca cell model.

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Vhl loss functionally upregulates HIF targets in the Renca cell model. ...
(A) Representative Western blot showing protein expression of VHL, HIF-1α, and actin in the indicated Renca cell lines. (B–E) Quantitative PCR of Glut1, Ldha, Pdk1, and Egln1 in the indicated cell lines relative to Vhl WT.2. Each data point represents a technical replicate from 2 independent experiments. Nuclear magnetic resonance (NMR) quantification of glucose uptake (F) and lactate secretion (G) from CM in Renca Vhl WT.1/KO.1 and Vhl WT.2/KO.7 paired cell lines. Each data point represents a technical replicate. (H) Representative images and quantification of CD31 IHC staining of Vhl WT.2 and Vhl-KO.7 subcutaneous tumors. Scale bars: 200 μm. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by ordinary 1-way ANOVA and Bonferroni’s multiple-comparison test (B–G) and 2-tailed Student’s t test (H).