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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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Research Article Metabolism Oncology Article has an altmetric score of 46

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

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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 6

Myeloid cells in the Vhl-KO TME are more glycolytic.

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Myeloid cells in the Vhl-KO TME are more glycolytic.
(A) Experimental wo...
(A) Experimental workflow for FDG PET imaging and characterization of FDG avid single-cell populations. (B) Representative FDG PET images of Vhl WT and Vhl-KO tumors, and quantification of whole tumor PET avidity of the indicated WT and KO pairs. (C) Representative flow cytometric gating of whole tumor and MDSC-enriched (anti-Gr1 microbead positive selection) and TAM-enriched (Gr1–, anti-CD11b microbead positive selection) populations. (D) Quantification of cellular FDG avidity in MDSC-enriched and TAM-enriched cell fractions from the indicated Vhl WT and Vhl-KO tumors. (E) Cellular FDG avidity of CD45– (anti-CD45 microbead negative selection) and CD3+ enriched (anti-CD4/CD8 microbead positive selection) T cells from the indicated Vhl WT or Vhl-KO tumors. (F) UMAP showing snRNA-Seq data from 3 human ccRCC patient tumors, and (G) KEGG pathway analysis for oxidative phosphorylation and glycolysis/gluconeogenesis in the designated cell populations. Each data point represents a biological replicate, and graphs show the mean ± SEM. *P < 0.05, **P < 0.01, and ****P < 0.0001, by unpaired, 2-tailed Student’s t test (B, D, and E) and Brown-Forsythe and Welch’s ANOVAs corrected with Games-Howell (G).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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