Cell-programmed nutrient partitioning in the tumour microenvironment

Bradley I. Reinfeld, Matthew Z. Madden, Melissa M. Wolf, Anna Chytil, Jackie E. Bader, Andrew R. Patterson, Ayaka Sugiura, Allison S. Cohen, Ahmed Ali, Brian T. Do, Alexander Muir, Caroline A. Lewis, Rachel A. Hongo, Kirsten L. Young, Rachel E. Brown, Vera M. Todd, Tessa Huffstater, Abin Abraham, Richard T. O’Neil, Matthew H. Wilson, Fuxue Xin, M. Noor Tantawy, W. David Merryman, Rachelle W. Johnson, Christopher S. Williams, Emily F. Mason, Frank M. Mason, Katherine E. Beckermann, Matthew G. Heiden, H. Charles Manning, Jeffrey C. Rathmell () and W. Kimryn Rathmell ()
Additional contact information
Bradley I. Reinfeld: Vanderbilt University
Matthew Z. Madden: Vanderbilt University
Melissa M. Wolf: Vanderbilt University Medical Center (VUMC)
Anna Chytil: Vanderbilt University Medical Center (VUMC)
Jackie E. Bader: Microbiology and Immunology, VUMC
Andrew R. Patterson: Microbiology and Immunology, VUMC
Ayaka Sugiura: Vanderbilt University
Allison S. Cohen: VUMC
Ahmed Ali: Massachusetts Institute of Technology (MIT)
Brian T. Do: Massachusetts Institute of Technology (MIT)
Alexander Muir: University of Chicago
Caroline A. Lewis: Whitehead Institute for Biomedical Research, MIT
Rachel A. Hongo: Vanderbilt University Medical Center (VUMC)
Kirsten L. Young: Vanderbilt University Medical Center (VUMC)
Rachel E. Brown: Vanderbilt University
Vera M. Todd: Vanderbilt University Medical Center (VUMC)
Tessa Huffstater: Vanderbilt University
Abin Abraham: Vanderbilt University
Richard T. O’Neil: Vanderbilt University Medical Center (VUMC)
Matthew H. Wilson: Vanderbilt University Medical Center (VUMC)
Fuxue Xin: VUMC
M. Noor Tantawy: VUMC
W. David Merryman: Vanderbilt University
Rachelle W. Johnson: Vanderbilt University Medical Center (VUMC)
Christopher S. Williams: Vanderbilt University Medical Center (VUMC)
Emily F. Mason: Microbiology and Immunology, VUMC
Frank M. Mason: Vanderbilt University Medical Center (VUMC)
Katherine E. Beckermann: Vanderbilt University Medical Center (VUMC)
Matthew G. Heiden: Massachusetts Institute of Technology (MIT)
H. Charles Manning: VUMC
Jeffrey C. Rathmell: Microbiology and Immunology, VUMC
W. Kimryn Rathmell: Vanderbilt University Medical Center (VUMC)

Nature, 2021, vol. 593, issue 7858, 282-288

Abstract: Abstract Cancer cells characteristically consume glucose through Warburg metabolism1, a process that forms the basis of tumour imaging by positron emission tomography (PET). Tumour-infiltrating immune cells also rely on glucose, and impaired immune cell metabolism in the tumour microenvironment (TME) contributes to immune evasion by tumour cells2–4. However, whether the metabolism of immune cells is dysregulated in the TME by cell-intrinsic programs or by competition with cancer cells for limited nutrients remains unclear. Here we used PET tracers to measure the access to and uptake of glucose and glutamine by specific cell subsets in the TME. Notably, myeloid cells had the greatest capacity to take up intratumoral glucose, followed by T cells and cancer cells, across a range of cancer models. By contrast, cancer cells showed the highest uptake of glutamine. This distinct nutrient partitioning was programmed in a cell-intrinsic manner through mTORC1 signalling and the expression of genes related to the metabolism of glucose and glutamine. Inhibiting glutamine uptake enhanced glucose uptake across tumour-resident cell types, showing that glutamine metabolism suppresses glucose uptake without glucose being a limiting factor in the TME. Thus, cell-intrinsic programs drive the preferential acquisition of glucose and glutamine by immune and cancer cells, respectively. Cell-selective partitioning of these nutrients could be exploited to develop therapies and imaging strategies to enhance or monitor the metabolic programs and activities of specific cell populations in the TME.

Date: 2021
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DOI: 10.1038/s41586-021-03442-1

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