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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 8

The myeloid CX3CL1/CX3CR1 axis is augmented in Vhl-deficient tumors.

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The myeloid CX3CL1/CX3CR1 axis is augmented in Vhl-deficient tumors.
(A)...
(A) Quantification of soluble CX3CL1 in Vhl WT.2, Vhl-KO.7, and Vhl CX3CL1-DKO CM by ELISA. Data represent technical replicates from 2 independent experiments and were normalized per 106 cells. (B) Relative monocyte migration stimulated by either SF media or CM from Vhl WT.2, Vhl-KO.7, or Vhl Cx3cl1-DKO cells. (C) Average growth curve of all Vhl-KO.7 (gray) and Vhl Cx3cl1-DKO (purple) tumors represented as tumor volume (mm3). Smaller graphs represent biological replicates. (D) Quantification of CD45+, CD11b+, and CD3+ immune infiltrate from Vhl WT, Vhl-KO, and Vhl Cx3cl1-DKO tumors. (E) Quantification of overall TAM, TAM1, and TAM2 infiltration as the percentage of viable cells in Vhl-KO and Vhl Cx3cl1-DKO tumors (F) Protein MFI quantification and representative histogram of CD11c and (G) CD206 in overall TAMs from Vhl WT.2, Vhl-KO.7, and Vhl Cx3cl1-DKO tumors. (H) Percentage of Phrodo+ cells as a fraction of viable CD45+CD11b+F4/80+ cells in Vhl WT.2 and Vhl-KO.7, and Vhl Cx3cl1-DKO tumors. (I) Ranked gene expression scores for CX3CL1 and (J) CX3CR1 across 30 nonlymphoid solid tumors queried in TCGA. Data represent biological replicates. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA with Bonferroni’s multiple-comparison test (A, B, D, F, and G), 2-way ANOVA with Šidák’s multiple-comparison test (C), and 2-tailed Student’s t test (E and H). Graphs show the mean ± SEM.

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

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