Research ArticleMetabolismOncology Open Access | 10.1172/JCI173934

Melissa M. Wolf,1,2 Matthew Z. Madden,1,3 Emily N. Arner,1 Jackie E. Bader,1 Xiang Ye,1 Logan Vlach,1,2 Megan L. Tigue,1,2,3 Madelyn D. Landis,4 Patrick B. Jonker,5 Zaid Hatem,1 KayLee K. Steiner,1,2 Dakim K. Gaines,6,7 Bradley I. Reinfeld,2,3,4 Emma S. Hathaway,1,2 Fuxue Xin,8,9 M. Noor Tantawy,8,9 Scott M. Haake,4,7 Eric Jonasch,10 Alexander Muir,5 Vivian L. Weiss,1,7 Kathryn E. Beckermann,4,7 W. Kimryn Rathmell,4,7,11 and Jeffrey C. Rathmell1,7,11

1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville (VUMC), Tennessee, USA.

2Graduate Program in Cancer Biology and

3Medical Scientist Training Program, Vanderbilt University, Nashville, Tennessee, USA.

4Department of Medicine, VUMC, Nashville, Tennessee, USA.

5Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA.

6Department of Radiation Oncology,

7Vanderbilt-Ingram Cancer Center,

8Department of Radiology and Radiological Sciences, and

9Vanderbilt University Institute of Imaging Science, VUMC, Nashville, Tennessee, USA.

10Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

11Vanderbilt Center for Immunobiology, VUMC, Nashville, Tennessee, USA.

Address correspondence to: Jeffrey Rathmell, Vanderbilt University Medical Center, 1161 21st Ave. South, Medical Center North, Rm B3301, Box 2510, Nashville, Tennessee 37232, USA. Phone: 919.619.0452; Email: jeff.rathmell@vumc.org.

Find articles by Wolf, M. in: JCI | PubMed | Google Scholar

1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville (VUMC), Tennessee, USA.

2Graduate Program in Cancer Biology and

3Medical Scientist Training Program, Vanderbilt University, Nashville, Tennessee, USA.

4Department of Medicine, VUMC, Nashville, Tennessee, USA.

5Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA.

6Department of Radiation Oncology,

7Vanderbilt-Ingram Cancer Center,

8Department of Radiology and Radiological Sciences, and

9Vanderbilt University Institute of Imaging Science, VUMC, Nashville, Tennessee, USA.

10Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

11Vanderbilt Center for Immunobiology, VUMC, Nashville, Tennessee, USA.

Address correspondence to: Jeffrey Rathmell, Vanderbilt University Medical Center, 1161 21st Ave. South, Medical Center North, Rm B3301, Box 2510, Nashville, Tennessee 37232, USA. Phone: 919.619.0452; Email: jeff.rathmell@vumc.org.

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1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville (VUMC), Tennessee, USA.

2Graduate Program in Cancer Biology and

3Medical Scientist Training Program, Vanderbilt University, Nashville, Tennessee, USA.

4Department of Medicine, VUMC, Nashville, Tennessee, USA.

5Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA.

6Department of Radiation Oncology,

7Vanderbilt-Ingram Cancer Center,

8Department of Radiology and Radiological Sciences, and

9Vanderbilt University Institute of Imaging Science, VUMC, Nashville, Tennessee, USA.

10Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

11Vanderbilt Center for Immunobiology, VUMC, Nashville, Tennessee, USA.

Address correspondence to: Jeffrey Rathmell, Vanderbilt University Medical Center, 1161 21st Ave. South, Medical Center North, Rm B3301, Box 2510, Nashville, Tennessee 37232, USA. Phone: 919.619.0452; Email: jeff.rathmell@vumc.org.

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1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville (VUMC), Tennessee, USA.

2Graduate Program in Cancer Biology and

3Medical Scientist Training Program, Vanderbilt University, Nashville, Tennessee, USA.

4Department of Medicine, VUMC, Nashville, Tennessee, USA.

5Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA.

6Department of Radiation Oncology,

7Vanderbilt-Ingram Cancer Center,

8Department of Radiology and Radiological Sciences, and

9Vanderbilt University Institute of Imaging Science, VUMC, Nashville, Tennessee, USA.

10Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

11Vanderbilt Center for Immunobiology, VUMC, Nashville, Tennessee, USA.

Address correspondence to: Jeffrey Rathmell, Vanderbilt University Medical Center, 1161 21st Ave. South, Medical Center North, Rm B3301, Box 2510, Nashville, Tennessee 37232, USA. Phone: 919.619.0452; Email: jeff.rathmell@vumc.org.

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1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville (VUMC), Tennessee, USA.

2Graduate Program in Cancer Biology and

3Medical Scientist Training Program, Vanderbilt University, Nashville, Tennessee, USA.

4Department of Medicine, VUMC, Nashville, Tennessee, USA.

5Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA.

6Department of Radiation Oncology,

7Vanderbilt-Ingram Cancer Center,

8Department of Radiology and Radiological Sciences, and

9Vanderbilt University Institute of Imaging Science, VUMC, Nashville, Tennessee, USA.

10Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

11Vanderbilt Center for Immunobiology, VUMC, Nashville, Tennessee, USA.

Address correspondence to: Jeffrey Rathmell, Vanderbilt University Medical Center, 1161 21st Ave. South, Medical Center North, Rm B3301, Box 2510, Nashville, Tennessee 37232, USA. Phone: 919.619.0452; Email: jeff.rathmell@vumc.org.

Find articles by Ye, X. in: JCI | PubMed | Google Scholar |

1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville (VUMC), Tennessee, USA.

2Graduate Program in Cancer Biology and

3Medical Scientist Training Program, Vanderbilt University, Nashville, Tennessee, USA.

4Department of Medicine, VUMC, Nashville, Tennessee, USA.

5Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA.

6Department of Radiation Oncology,

7Vanderbilt-Ingram Cancer Center,

8Department of Radiology and Radiological Sciences, and

9Vanderbilt University Institute of Imaging Science, VUMC, Nashville, Tennessee, USA.

10Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

11Vanderbilt Center for Immunobiology, VUMC, Nashville, Tennessee, USA.

Address correspondence to: Jeffrey Rathmell, Vanderbilt University Medical Center, 1161 21st Ave. South, Medical Center North, Rm B3301, Box 2510, Nashville, Tennessee 37232, USA. Phone: 919.619.0452; Email: jeff.rathmell@vumc.org.

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1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville (VUMC), Tennessee, USA.

2Graduate Program in Cancer Biology and

3Medical Scientist Training Program, Vanderbilt University, Nashville, Tennessee, USA.

4Department of Medicine, VUMC, Nashville, Tennessee, USA.

5Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA.

6Department of Radiation Oncology,

7Vanderbilt-Ingram Cancer Center,

8Department of Radiology and Radiological Sciences, and

9Vanderbilt University Institute of Imaging Science, VUMC, Nashville, Tennessee, USA.

10Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

11Vanderbilt Center for Immunobiology, VUMC, Nashville, Tennessee, USA.

Address correspondence to: Jeffrey Rathmell, Vanderbilt University Medical Center, 1161 21st Ave. South, Medical Center North, Rm B3301, Box 2510, Nashville, Tennessee 37232, USA. Phone: 919.619.0452; Email: jeff.rathmell@vumc.org.

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1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville (VUMC), Tennessee, USA.

2Graduate Program in Cancer Biology and

3Medical Scientist Training Program, Vanderbilt University, Nashville, Tennessee, USA.

4Department of Medicine, VUMC, Nashville, Tennessee, USA.

5Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA.

6Department of Radiation Oncology,

7Vanderbilt-Ingram Cancer Center,

8Department of Radiology and Radiological Sciences, and

9Vanderbilt University Institute of Imaging Science, VUMC, Nashville, Tennessee, USA.

10Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

11Vanderbilt Center for Immunobiology, VUMC, Nashville, Tennessee, USA.

Address correspondence to: Jeffrey Rathmell, Vanderbilt University Medical Center, 1161 21st Ave. South, Medical Center North, Rm B3301, Box 2510, Nashville, Tennessee 37232, USA. Phone: 919.619.0452; Email: jeff.rathmell@vumc.org.

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1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville (VUMC), Tennessee, USA.

2Graduate Program in Cancer Biology and

3Medical Scientist Training Program, Vanderbilt University, Nashville, Tennessee, USA.

4Department of Medicine, VUMC, Nashville, Tennessee, USA.

5Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA.

6Department of Radiation Oncology,

7Vanderbilt-Ingram Cancer Center,

8Department of Radiology and Radiological Sciences, and

9Vanderbilt University Institute of Imaging Science, VUMC, Nashville, Tennessee, USA.

10Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

11Vanderbilt Center for Immunobiology, VUMC, Nashville, Tennessee, USA.

Address correspondence to: Jeffrey Rathmell, Vanderbilt University Medical Center, 1161 21st Ave. South, Medical Center North, Rm B3301, Box 2510, Nashville, Tennessee 37232, USA. Phone: 919.619.0452; Email: jeff.rathmell@vumc.org.

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1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville (VUMC), Tennessee, USA.

2Graduate Program in Cancer Biology and

3Medical Scientist Training Program, Vanderbilt University, Nashville, Tennessee, USA.

4Department of Medicine, VUMC, Nashville, Tennessee, USA.

5Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA.

6Department of Radiation Oncology,

7Vanderbilt-Ingram Cancer Center,

8Department of Radiology and Radiological Sciences, and

9Vanderbilt University Institute of Imaging Science, VUMC, Nashville, Tennessee, USA.

10Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

11Vanderbilt Center for Immunobiology, VUMC, Nashville, Tennessee, USA.

Address correspondence to: Jeffrey Rathmell, Vanderbilt University Medical Center, 1161 21st Ave. South, Medical Center North, Rm B3301, Box 2510, Nashville, Tennessee 37232, USA. Phone: 919.619.0452; Email: jeff.rathmell@vumc.org.

Find articles by Hatem, Z. in: JCI | PubMed | Google Scholar

1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville (VUMC), Tennessee, USA.

2Graduate Program in Cancer Biology and

3Medical Scientist Training Program, Vanderbilt University, Nashville, Tennessee, USA.

4Department of Medicine, VUMC, Nashville, Tennessee, USA.

5Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA.

6Department of Radiation Oncology,

7Vanderbilt-Ingram Cancer Center,

8Department of Radiology and Radiological Sciences, and

9Vanderbilt University Institute of Imaging Science, VUMC, Nashville, Tennessee, USA.

10Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

11Vanderbilt Center for Immunobiology, VUMC, Nashville, Tennessee, USA.

Address correspondence to: Jeffrey Rathmell, Vanderbilt University Medical Center, 1161 21st Ave. South, Medical Center North, Rm B3301, Box 2510, Nashville, Tennessee 37232, USA. Phone: 919.619.0452; Email: jeff.rathmell@vumc.org.

Find articles by Steiner, K. in: JCI | PubMed | Google Scholar

1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville (VUMC), Tennessee, USA.

2Graduate Program in Cancer Biology and

3Medical Scientist Training Program, Vanderbilt University, Nashville, Tennessee, USA.

4Department of Medicine, VUMC, Nashville, Tennessee, USA.

5Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA.

6Department of Radiation Oncology,

7Vanderbilt-Ingram Cancer Center,

8Department of Radiology and Radiological Sciences, and

9Vanderbilt University Institute of Imaging Science, VUMC, Nashville, Tennessee, USA.

10Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

11Vanderbilt Center for Immunobiology, VUMC, Nashville, Tennessee, USA.

Address correspondence to: Jeffrey Rathmell, Vanderbilt University Medical Center, 1161 21st Ave. South, Medical Center North, Rm B3301, Box 2510, Nashville, Tennessee 37232, USA. Phone: 919.619.0452; Email: jeff.rathmell@vumc.org.

Find articles by Gaines, D. in: JCI | PubMed | Google Scholar

1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville (VUMC), Tennessee, USA.

2Graduate Program in Cancer Biology and

3Medical Scientist Training Program, Vanderbilt University, Nashville, Tennessee, USA.

4Department of Medicine, VUMC, Nashville, Tennessee, USA.

5Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA.

6Department of Radiation Oncology,

7Vanderbilt-Ingram Cancer Center,

8Department of Radiology and Radiological Sciences, and

9Vanderbilt University Institute of Imaging Science, VUMC, Nashville, Tennessee, USA.

10Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

11Vanderbilt Center for Immunobiology, VUMC, Nashville, Tennessee, USA.

Address correspondence to: Jeffrey Rathmell, Vanderbilt University Medical Center, 1161 21st Ave. South, Medical Center North, Rm B3301, Box 2510, Nashville, Tennessee 37232, USA. Phone: 919.619.0452; Email: jeff.rathmell@vumc.org.

Find articles by Reinfeld, B. in: JCI | PubMed | Google Scholar

1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville (VUMC), Tennessee, USA.

2Graduate Program in Cancer Biology and

3Medical Scientist Training Program, Vanderbilt University, Nashville, Tennessee, USA.

4Department of Medicine, VUMC, Nashville, Tennessee, USA.

5Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA.

6Department of Radiation Oncology,

7Vanderbilt-Ingram Cancer Center,

8Department of Radiology and Radiological Sciences, and

9Vanderbilt University Institute of Imaging Science, VUMC, Nashville, Tennessee, USA.

10Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

11Vanderbilt Center for Immunobiology, VUMC, Nashville, Tennessee, USA.

Address correspondence to: Jeffrey Rathmell, Vanderbilt University Medical Center, 1161 21st Ave. South, Medical Center North, Rm B3301, Box 2510, Nashville, Tennessee 37232, USA. Phone: 919.619.0452; Email: jeff.rathmell@vumc.org.

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1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville (VUMC), Tennessee, USA.

2Graduate Program in Cancer Biology and

3Medical Scientist Training Program, Vanderbilt University, Nashville, Tennessee, USA.

4Department of Medicine, VUMC, Nashville, Tennessee, USA.

5Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA.

6Department of Radiation Oncology,

7Vanderbilt-Ingram Cancer Center,

8Department of Radiology and Radiological Sciences, and

9Vanderbilt University Institute of Imaging Science, VUMC, Nashville, Tennessee, USA.

10Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

11Vanderbilt Center for Immunobiology, VUMC, Nashville, Tennessee, USA.

Address correspondence to: Jeffrey Rathmell, Vanderbilt University Medical Center, 1161 21st Ave. South, Medical Center North, Rm B3301, Box 2510, Nashville, Tennessee 37232, USA. Phone: 919.619.0452; Email: jeff.rathmell@vumc.org.

Find articles by Xin, F. in: JCI | PubMed | Google Scholar

1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville (VUMC), Tennessee, USA.

2Graduate Program in Cancer Biology and

3Medical Scientist Training Program, Vanderbilt University, Nashville, Tennessee, USA.

4Department of Medicine, VUMC, Nashville, Tennessee, USA.

5Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA.

6Department of Radiation Oncology,

7Vanderbilt-Ingram Cancer Center,

8Department of Radiology and Radiological Sciences, and

9Vanderbilt University Institute of Imaging Science, VUMC, Nashville, Tennessee, USA.

10Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

11Vanderbilt Center for Immunobiology, VUMC, Nashville, Tennessee, USA.

Address correspondence to: Jeffrey Rathmell, Vanderbilt University Medical Center, 1161 21st Ave. South, Medical Center North, Rm B3301, Box 2510, Nashville, Tennessee 37232, USA. Phone: 919.619.0452; Email: jeff.rathmell@vumc.org.

Find articles by Tantawy, M. in: JCI | PubMed | Google Scholar

1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville (VUMC), Tennessee, USA.

2Graduate Program in Cancer Biology and

3Medical Scientist Training Program, Vanderbilt University, Nashville, Tennessee, USA.

4Department of Medicine, VUMC, Nashville, Tennessee, USA.

5Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA.

6Department of Radiation Oncology,

7Vanderbilt-Ingram Cancer Center,

8Department of Radiology and Radiological Sciences, and

9Vanderbilt University Institute of Imaging Science, VUMC, Nashville, Tennessee, USA.

10Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

11Vanderbilt Center for Immunobiology, VUMC, Nashville, Tennessee, USA.

Address correspondence to: Jeffrey Rathmell, Vanderbilt University Medical Center, 1161 21st Ave. South, Medical Center North, Rm B3301, Box 2510, Nashville, Tennessee 37232, USA. Phone: 919.619.0452; Email: jeff.rathmell@vumc.org.

Find articles by Haake, S. in: JCI | PubMed | Google Scholar |

1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville (VUMC), Tennessee, USA.

2Graduate Program in Cancer Biology and

3Medical Scientist Training Program, Vanderbilt University, Nashville, Tennessee, USA.

4Department of Medicine, VUMC, Nashville, Tennessee, USA.

5Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA.

6Department of Radiation Oncology,

7Vanderbilt-Ingram Cancer Center,

8Department of Radiology and Radiological Sciences, and

9Vanderbilt University Institute of Imaging Science, VUMC, Nashville, Tennessee, USA.

10Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

11Vanderbilt Center for Immunobiology, VUMC, Nashville, Tennessee, USA.

Address correspondence to: Jeffrey Rathmell, Vanderbilt University Medical Center, 1161 21st Ave. South, Medical Center North, Rm B3301, Box 2510, Nashville, Tennessee 37232, USA. Phone: 919.619.0452; Email: jeff.rathmell@vumc.org.

Find articles by Jonasch, E. in: JCI | PubMed | Google Scholar

1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville (VUMC), Tennessee, USA.

2Graduate Program in Cancer Biology and

3Medical Scientist Training Program, Vanderbilt University, Nashville, Tennessee, USA.

4Department of Medicine, VUMC, Nashville, Tennessee, USA.

5Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA.

6Department of Radiation Oncology,

7Vanderbilt-Ingram Cancer Center,

8Department of Radiology and Radiological Sciences, and

9Vanderbilt University Institute of Imaging Science, VUMC, Nashville, Tennessee, USA.

10Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

11Vanderbilt Center for Immunobiology, VUMC, Nashville, Tennessee, USA.

Address correspondence to: Jeffrey Rathmell, Vanderbilt University Medical Center, 1161 21st Ave. South, Medical Center North, Rm B3301, Box 2510, Nashville, Tennessee 37232, USA. Phone: 919.619.0452; Email: jeff.rathmell@vumc.org.

Find articles by Muir, A. in: JCI | PubMed | Google Scholar

1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville (VUMC), Tennessee, USA.

2Graduate Program in Cancer Biology and

3Medical Scientist Training Program, Vanderbilt University, Nashville, Tennessee, USA.

4Department of Medicine, VUMC, Nashville, Tennessee, USA.

5Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA.

6Department of Radiation Oncology,

7Vanderbilt-Ingram Cancer Center,

8Department of Radiology and Radiological Sciences, and

9Vanderbilt University Institute of Imaging Science, VUMC, Nashville, Tennessee, USA.

10Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

11Vanderbilt Center for Immunobiology, VUMC, Nashville, Tennessee, USA.

Address correspondence to: Jeffrey Rathmell, Vanderbilt University Medical Center, 1161 21st Ave. South, Medical Center North, Rm B3301, Box 2510, Nashville, Tennessee 37232, USA. Phone: 919.619.0452; Email: jeff.rathmell@vumc.org.

Find articles by Weiss, V. in: JCI | PubMed | Google Scholar

1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville (VUMC), Tennessee, USA.

2Graduate Program in Cancer Biology and

3Medical Scientist Training Program, Vanderbilt University, Nashville, Tennessee, USA.

4Department of Medicine, VUMC, Nashville, Tennessee, USA.

5Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA.

6Department of Radiation Oncology,

7Vanderbilt-Ingram Cancer Center,

8Department of Radiology and Radiological Sciences, and

9Vanderbilt University Institute of Imaging Science, VUMC, Nashville, Tennessee, USA.

10Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

11Vanderbilt Center for Immunobiology, VUMC, Nashville, Tennessee, USA.

Address correspondence to: Jeffrey Rathmell, Vanderbilt University Medical Center, 1161 21st Ave. South, Medical Center North, Rm B3301, Box 2510, Nashville, Tennessee 37232, USA. Phone: 919.619.0452; Email: jeff.rathmell@vumc.org.

Find articles by Beckermann, K. in: JCI | PubMed | Google Scholar

1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville (VUMC), Tennessee, USA.

2Graduate Program in Cancer Biology and

3Medical Scientist Training Program, Vanderbilt University, Nashville, Tennessee, USA.

4Department of Medicine, VUMC, Nashville, Tennessee, USA.

5Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA.

6Department of Radiation Oncology,

7Vanderbilt-Ingram Cancer Center,

8Department of Radiology and Radiological Sciences, and

9Vanderbilt University Institute of Imaging Science, VUMC, Nashville, Tennessee, USA.

10Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

11Vanderbilt Center for Immunobiology, VUMC, Nashville, Tennessee, USA.

Address correspondence to: Jeffrey Rathmell, Vanderbilt University Medical Center, 1161 21st Ave. South, Medical Center North, Rm B3301, Box 2510, Nashville, Tennessee 37232, USA. Phone: 919.619.0452; Email: jeff.rathmell@vumc.org.

Find articles by Rathmell, W. in: JCI | PubMed | Google Scholar |

1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville (VUMC), Tennessee, USA.

2Graduate Program in Cancer Biology and

3Medical Scientist Training Program, Vanderbilt University, Nashville, Tennessee, USA.

4Department of Medicine, VUMC, Nashville, Tennessee, USA.

5Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA.

6Department of Radiation Oncology,

7Vanderbilt-Ingram Cancer Center,

8Department of Radiology and Radiological Sciences, and

9Vanderbilt University Institute of Imaging Science, VUMC, Nashville, Tennessee, USA.

10Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

11Vanderbilt Center for Immunobiology, VUMC, Nashville, Tennessee, USA.

Address correspondence to: Jeffrey Rathmell, Vanderbilt University Medical Center, 1161 21st Ave. South, Medical Center North, Rm B3301, Box 2510, Nashville, Tennessee 37232, USA. Phone: 919.619.0452; Email: jeff.rathmell@vumc.org.

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Published April 15, 2024 - More info

Published in Volume 134, Issue 8 on April 15, 2024
J Clin Invest. 2024;134(8):e173934. https://doi.org/10.1172/JCI173934.
© 2024 Wolf et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Published April 15, 2024 - Version history
Received: July 19, 2023; Accepted: February 24, 2024 View PDF 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.

Graphical Abstract Introduction

Clear cell renal cell carcinoma (ccRCC) represents the most frequent subtype of RCC, accounting for approximately 75% of adult clinical cases (1, 2). ccRCC biology is unique due to near-ubiquitous loss of function of the von Hippel Lindau (VHL) gene, the truncal event in the progression of ccRCC that causes alterations in cellular hypoxia sensing and regulation (2–4). In oxygen-depleted environments or if VHL is inactive, HIF proteins are rapidly stabilized and carry out transcriptional upregulation of hypoxia response pathways including angiogenesis and aerobic glycolysis (5). VHL loss thus promotes a pseudohypoxic state resulting in characteristic patterns of dysregulated blood vessel formation and may promote shifts in regional nutrient availability and locoregional cellular metabolism (6).

ccRCC tumors have a high frequency of CD8+ and CD4+ T cells in the tumor microenvironment (TME), making them a favorable candidate for immune checkpoint blockade therapy (ICB) (7, 8). Yet, responsiveness to ICB is variable, and the exact mechanisms that determine responsiveness are not well understood (9–11). Tumor-associated macrophages (TAMs), monocytic and polymorphonuclear myeloid–derived suppressor cells (M-MDSCs and PMN-MDSCs), NK cells, and DCs are other key components of the innate TME that can exert pro- and/or antitumorigenic functions depending on the environment (12, 13). Factors that give rise to lymphoid and myeloid infiltration and fate vary among cancer types for reasons that are poorly understood. In ccRCC, T cells and TAMs are on average the 2 most frequent immune cell populations residing in the TME (13); yet, independent of T cell characteristics, myeloid inflammation has only recently been identified as critical in the development of metastatic ccRCC (14, 15).

Increased glucose uptake in cancer is a common feature used clinically by PET imaging to determine and track disease progression. It is now appreciated that immune and nonimmune cell subsets differ in their capacity to consume nutrients, including glucose, in a tumor setting. Tumor-infiltrating myeloid cells preferentially consume glucose, whereas cancer cells, at least in murine models, have a preference for glutamine uptake (16). However, given the VHL/HIF–mediated axis leading to a robust upregulation in cancer cell aerobic glycolysis, it is possible that VHL-deleted ccRCC cancer cells are an exception to this finding so that glucose competition may occur in the TME. Therefore, it is unknown whether VHL loss engages reprogramming of the composition of the TME and/or function via metabolic or other functional mechanisms related to constitutive activation of hypoxia response pathways. Appreciation of the effect of VHL loss on metabolism and immune infiltration in a tumor setting may provide new opportunities for targeting the TME in ccRCC.

To answer this question, we used the Renca-immunocompetent murine model of kidney cancer, in which we manipulated the Vhl axis in vitro to explore the effects on the immune cell repertoire and function in vivo. We found that Vhl loss promoted less proliferative tumors and a selective immune microenvironment rich in conventional and regulatory CD4+ T cells as well as a distinct subset of TAMs with an increased capacity to consume glucose. Vhl-deficient tumors showed minimal response to ICB therapy by day 17, and T cells residing in Vhl-deficient tumors expressed fewer markers of dysfunction and effector cytokines when stimulated relative to Vhl WT tumors. Interestingly, Vhl loss resulted in increased cancer cell production of the cytokine CX3CL1, and deletion of Cx3cl1, together with Vhl, led to slower tumor growth and decreased myeloid infiltration associated with Vhl loss. Together, these findings demonstrate the importance of tumor-specific genetic alterations as a mechanism for reprogramming the immune landscape in cancer and highlight p-VHL loss–mediated CX3CL1 upregulation as a specific driver of myeloid inflammation in ccRCC.

Results

Lymphocytes and macrophages are abundant in ccRCC. Recent pan-cancer analyses have identified enhanced infiltration of lymphoid and myeloid immune subsets in ccRCC tumors (17, 18). ccRCC exhibits high gene expression of the pan-TAM marker CD68, as well as CD8A and CD4 T cell markers from The Cancer Genome Atlas (TCGA) database (Figure 1, A–C). Expression levels of CD68, representing all TAMs, and of CD4 were consistently and highly expressed throughout all stages of tumor progression, whereas CD8A expression was increased in later disease stages (Figure 1, A–C). Protein expression observed by high-dimensional multiplex imaging