TY - JOUR
T1 - Metabolic support of tumour-infiltrating regulatory T cells by lactic acid
AU - Watson, McLane L.J.
AU - Vignali, Paolo D.A.
AU - Mullett, Steven J.
AU - Overacre-Delgoffe, Abigail E.
AU - Peralta, Ronal M.
AU - Grebinoski, Stephanie
AU - Menk, Ashley V.
AU - Rittenhouse, Natalie L.
AU - DePeaux, Kristin
AU - Whetstone, Ryan D.
AU - Vignali, Dario A.A.
AU - Hand, Timothy W.
AU - Poholek, Amanda C.
AU - Morrison, Brett M.
AU - Rothstein, Jeffrey D.
AU - Wendell, Stacy G.
AU - Delgoffe, Greg M.
N1 - Funding Information:
Acknowledgements We thank A. Burton and C. Workman for the generation and gift of Foxp3FlpO-Ametrine mice, and G. Camirand for the gift of OT-II Foxp3RFP Thy1.1+ spleens. This work was supported by the Sidney Kimmel Foundation; a National Institutes of Health (NIH) Director’s New Innovator Award (DP2AI136598); the Hillman Fellows for Innovative Cancer Research Program; a Stand Up to Cancer–American Association for Cancer Research Innovative Research Grant (SU2C-AACR-IRG-04-16); the Alliance for Cancer Gene Therapy; the UPMC Hillman Cancer Center Skin Cancer and Head and Neck Cancer SPOREs (P50CA121973 and P50CA097190; NIH); the Mark Foundation for Cancer Research’s Emerging Leader Award; a Cancer Research Institute’s Lloyd J. Old STAR Award; and the Sy Holzer Endowed Immunotherapy Fund (all to G.M.D.). D.A.A.V. is supported by grants R01DK089125, R01CA203689 and P01AI108545 (all NIH). Trainees on this manuscript were supported by grants T32CA082084 (NIH) (to M.J.W., P.D.A.V., A.E.O.-D. and K.D.), F31AI149971 (NIH) (to M.J.W.), F30CA247034 (NIH) (to P.D.A.V.), F31CA247129 (NIH) (to K.D.), T32AI089443 (NIH) (to R.M.P and S.G.), F31AI147638 (NIH) (to S.G.), and a Damon Runyon Cancer Research Fellowship (to A.E.O.-D.). Mass spectrometry was supported by grant S10OD023402 (NIH) (to S.G.W.), and floxed animal generation was supported by grants R01NS099320 (NIH) (to J.D.R. and B.M.M). and R01 NS086818 (NIH) (to B.M.M.). Synthesis of GlucoseCy5 was supported by grant R21AI135367 (NIH) (to G.M.D.). Sequencing was supported by the Samuel and Emma Winters Foundation and a Grand Prize Award Grant (2017) from the Immuno-Oncology Young Investigators’ Forum (both to G.M.D.) and was performed at the University of Pittsburgh Health Sciences Sequencing Core at the Children’s Hospital of Pittsburgh. RNA-seq analysis was supported in part by the University of Pittsburgh Center for Research Computing through the resources provided. This work used the UPMC Hillman Cancer Center Flow Cytometry and Animal Facilities, supported in part by grant P30CA047904 (NIH).
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/3/25
Y1 - 2021/3/25
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85101489356&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85101489356&partnerID=8YFLogxK
U2 - 10.1038/s41586-020-03045-2
DO - 10.1038/s41586-020-03045-2
M3 - Article
C2 - 33589820
AN - SCOPUS:85101489356
VL - 591
SP - 645
EP - 651
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7851
ER -