Metabolic support of tumour-infiltrating regulatory T cells by lactic acid

McLane J. Watson, Paolo D. A. Vignali, Steven J. Mullett, Abigail E. Overacre-Delgoffe, Ronal M. Peralta, Stephanie Grebinoski, Ashley V. Menk, Natalie L. Rittenhouse, Kristin DePeaux, Ryan D. Whetstone, Dario A. A. Vignali, Timothy W. Hand, Amanda C. Poholek, Brett M. Morrison, Jeffrey D. Rothstein, Stacy G. Wendell and Greg M. Delgoffe ()
Additional contact information
McLane J. Watson: University of Pittsburgh
Paolo D. A. Vignali: University of Pittsburgh
Steven J. Mullett: University of Pittsburgh
Abigail E. Overacre-Delgoffe: University of Pittsburgh
Ronal M. Peralta: University of Pittsburgh
Stephanie Grebinoski: University of Pittsburgh
Ashley V. Menk: UPMC Hillman Cancer Center
Natalie L. Rittenhouse: UPMC Children’s Hospital of Pittsburgh
Kristin DePeaux: University of Pittsburgh
Ryan D. Whetstone: University of Pittsburgh
Dario A. A. Vignali: University of Pittsburgh
Timothy W. Hand: UPMC Children’s Hospital of Pittsburgh
Amanda C. Poholek: UPMC Children’s Hospital of Pittsburgh
Brett M. Morrison: Johns Hopkins University School of Medicine
Jeffrey D. Rothstein: Johns Hopkins University School of Medicine
Stacy G. Wendell: University of Pittsburgh
Greg M. Delgoffe: University of Pittsburgh

Nature, 2021, vol. 591, issue 7851, 645-651

Abstract: Abstract Regulatory T (Treg) cells, although vital for immune homeostasis, also represent a major barrier to anti-cancer immunity, as the tumour microenvironment (TME) promotes the recruitment, differentiation and activity of these cells1,2. Tumour cells show deregulated metabolism, leading to a metabolite-depleted, hypoxic and acidic TME3, which places infiltrating effector T cells in competition with the tumour for metabolites and impairs their function4–6. At the same time, Treg cells maintain a strong suppression of effector T cells within the TME7,8. As previous studies suggested that Treg cells possess a distinct metabolic profile from effector T cells9–11, we hypothesized that the altered metabolic landscape of the TME and increased activity of intratumoral Treg cells are linked. Here we show that Treg cells display broad heterogeneity in their metabolism of glucose within normal and transformed tissues, and can engage an alternative metabolic pathway to maintain suppressive function and proliferation. Glucose uptake correlates with poorer suppressive function and long-term instability, and high-glucose conditions impair the function and stability of Treg cells in vitro. Treg cells instead upregulate pathways involved in the metabolism of the glycolytic by-product lactic acid. Treg cells withstand high-lactate conditions, and treatment with lactate prevents the destabilizing effects of high-glucose conditions, generating intermediates necessary for proliferation. Deletion of MCT1—a lactate transporter—in Treg cells reveals that lactate uptake is dispensable for the function of peripheral Treg cells but required intratumorally, resulting in slowed tumour growth and an increased response to immunotherapy. Thus, Treg cells are metabolically flexible: they can use ‘alternative’ metabolites in the TME to maintain their suppressive identity. Further, our results suggest that tumours avoid destruction by not only depriving effector T cells of nutrients, but also metabolically supporting regulatory populations.

Date: 2021
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DOI: 10.1038/s41586-020-03045-2

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