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.
The Journal of clinical investigation. 2024 Apr 15*** epublish ***
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
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville (VUMC), Tennessee, USA., Department of Medicine, VUMC, Nashville, Tennessee, USA., Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA., Department of Radiation Oncology., Graduate Program in Cancer Biology and., Department of Radiology and Radiological Sciences, and., Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.