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 function4,5,6. 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 cells9,10,11, 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.
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Data availability
RNA-seq data that support the findings of this study (Fig. 2b, h) have been deposited in the Gene Expression Omnibus (GEO; https://www.ncbi.nlm.nih.gov/geo/) under accession number GSE158801. The data supporting the findings of this study are available within the paper and the Extended Data figures. Source data are provided with this paper.
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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).
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M.J.W. performed most of the experiments, analysed data, and wrote the manuscript. P.D.A.V. helped to perform isotopic flux analysis and suppression assays, and contributed to writing. S.J.M. performed and analysed isotopic flux experiments. A.E.O.-D. carried out the transfer colitis experiments. R.M.P. performed in vitro differentiation and suppression assays. S.G. helped to purify and analyse cells from NOD mice. A.V.M. performed extracellular flux analysis and tumour histology analysis. N.L.R. analysed RNA-seq data. K.D. performed various in vitro experiments. R.D.W. sorted cells for isotopic flux analysis and RNA sequencing. D.A.A.V. provided Foxp3FlpO-Ametrine and NOD.Foxp3GFP mice and scientific insight. B.M.M. and J.D.R. generated and provided Slc16a1f/f mice and scientific insight. T.W.H. provided insight and facilities for transfer colitis experiments. A.C.P. helped to perform and analyse RNA-seq experiments. S.G.W. oversaw analysis of isotopic flux data. G.M.D. conceived of the study, carried out initial experiments, obtained funding, and wrote the manuscript.
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Extended data figures and tables
Extended Data Fig. 1 GlucoseCy5 can act as a surrogate for 2NBDG in GFP/YFP Treg reporter mice.
a, Gating strategy for sorting and analysis of Treg and Tconv cells. b, Representative plot showing the percentage of Treg (CD4+ Foxp3+) cells in the lymph nodes (LN) and tumours (tumour-infiltrating lymphocytes, TILs) of B16-bearing C57BL/6 mice 14 days after tumour inoculation. Representative plots are shown, gated on total CD4+ cells; percentages are shown within the plots. c, ECAR of Treg (Foxp3+) and Tconv (Foxp3−) cells sorted from LN and B16 TIL preparations as in b, 48 h after activation with anti-CD3/CD28 antibodies and IL-2. ΔECAR, maximum reading after treatment with glucose minus basal ECAR. Max ECAR, maximum reading after treatment with oligomycin minus basal ECAR. d, Ex vivo 2NBDG uptake, measured by mean fluorescence intensity (MFI), by Treg, Tconv and CD8+ T cells from the LN and B16 TILs. **P = 0.0045. e, Ex vivo 2NBDG uptake by CD44+ CD62L– and CD44– CD62L+ Treg and Tconv cells isolated from the LN of Foxp3-Ametrine reporter mice. f, Lymphocytes from Foxp3-Ametrine reporter mice were simultaneously pulsed with 2NBDG and GlucoseCy5. Shown is a representative plot, gated for CD4+ Foxp3+ cells, with tabulation of the percentage of GlucoseCy5+ cells among 2NBDG+ Treg cells. g, Ex vivo GlucoseCy5 uptake by CD44+ Treg and Tconv cells from the LN and B16 TILs. Shown are representative plots gated on CD44+ CD4+ cells. **P = 0.0025. h, GlucoseCy5 positivity in Nrp1– and Nrp+ Treg cells. i, Ex vivo GlucoseCy5 uptake by Tconv cells isolated from various tissues. Results are representative of three (a–d, f–i) or two (e) independent experiments. Significance (*P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001) was determined by paired two-tailed t-test (e), unpaired two-tailed t-test (d, f–h) or two-way ANOVA with Sidak’s multiple comparisons test (c). Data are means ± s.e.m. from biological replicates.
Extended Data Fig. 2 Glucose-avid Treg cells harbour a weaker Treg signature but retain viability and some suppressor activity.
a, Treg cells were sorted on the basis of GlucoseCy5 uptake and assayed for their ability to suppress the proliferation of CTV-labelled Tconv cells at a ratio of 1:4 (Treg:Tconv). LN, *P = 0.02; TIL, *P = 0.041. b, Experimental protocol for c, d. c, Representative histogram and quantification of viability of sorted 2NBDGhi and 2NBDGlo Treg cells after 72 h in a suppression assay. d, 2NBDG uptake by 2NBDGhi or 2NBDGlo Treg cells as in b. e, Representative histograms and tabulation of the expression of Treg signature genes in 2NBDGlo and 2NBDGhi Treg subsets. Nrp1, **P = 0.0016; CD73, *P = 0.029, **P = 0.0076; TIGIT LN, *P = 0.04; TIL, *P = 0.016; CD25, *P = 0.037. f, Weights of Rag1–/– mice that received an adoptive transfer of either 2NBDGlo or 2NBDGhi Treg cells plus Thy1.1+ Tconv cells intravenously. g, Representative histogram showing the proliferation of Tconv responder cells after 72 h of co-culture with Treg cells (1:4) conditioned in 0 mM, 5 mM or 25 mM glucose for 3 days. The suppression assay occurred in 25 mM glucose. NS, no stimulation; no TR, no Treg cells. h, Gene set enrichment plot of cellular lipid catabolic processes from TIL 2NBDGhi vs 2NBDGlo Treg cells. GO, Gene Ontology; NES, normalized enrichment score. Nom. p, nominal P value. i, Expression of Slc16a1 and Ldha mRNA in LN- and B16-infiltrating Treg and Tconv cells by qPCR. Ldha, **P = 0.004; Slc16a1, **P = 0.009. j, Expression of Slc16a1 and Ldha mRNA in Treg or Tconv cells activated overnight and conditioned in the glucose concentrations indicated for 3 days (normalized to 25 mM glucose; significance determined by comparing Treg and Tconv). Ldha, **P = 0.002; Slc16a1 plus 5 mM glucose, *P = 0.030; Slc16a1 plus 0 mM glucose, *P = 0.046. Results are representative of three (a, e, h–j), or two (c–f) independent experiments. Significance (*P < 0.05, **P < 0.01, ***P < 0.001) was determined by unpaired two-tailed t-test (a, f, i, j), paired two-tailed t-test (c, d) or two-way ANOVA with Sidak’s multiple comparisons test (e). Data are means ± s.e.m. from biological replicates.
Extended Data Fig. 3 Treg cells are resistant to lactic acid and use PEPCK-mediated metabolic pathways to support their proliferation.
a, Proliferation of CD8+, Tconv and Treg CTV-labelled cells activated in media comprising lactic acid for three days. **P = 0.0058. b, Production of IFNγ by CD8+ and Tconv cells conditioned as in a and then restimulated overnight with PMA/ionomycin. CD8, **P = 0.0042; Tconv, *P = 0.02. c, Suppression assay carried out using Treg cells conditioned as in a. Supp:Resp, suppressor (Treg) to responder (Tconv) cell ratio. d, Representative histogram and quantification of pHrodo+ Treg cells taking up 2NBDG. e, Representative flow plot of Ki67 expression by B16-infiltrating Treg cells from mice treated with or without 3MP for 3 days. f, Suppressive capacity of Treg cells, isolated from mice as in Fig. 3k. g, Percentage of Foxp3+ cells, Tconv:Treg ratio, and CD8+:Treg ratio within the TILs of mice treated as in f. ns, not significant. h, Growth curve of B16 melanoma in C57BL/6 mice treated with water or 3MP. i, Proliferation of Treg and Tconv cells activated and cultured in 10 mM lactic acid with or without 3MP for 3 days. *P = 0.016. j, Capacity of activated Treg cells conditioned in 10 mM lactic acid with or without 250 μM 3MP for 3 days to suppress the proliferation of CTV-labelled Tconv cells. k, IFNγ expression by CD8+ and Tconv cells in Foxp3Cre or Slc16a1f/fFoxp3Cre mice treated as in f. l, Percentage of Foxp3+ cells, Tconv:Treg ratio, and CD8+:Treg ratio within LN and tumours of Slc16a1f/fFoxp3Cre mice treated as in f. Results are representative of four (d), three (a–c, f, g, i) or two (h, j, k, l) independent experiments. Significance (*P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001) was determined by unpaired two-tailed t-test (d, g, i, k, l), one-way ANOVA with Dunnett’s multiple comparisons test (a, b) or two-way ANOVA with Sidak’s multiple comparisons test (c, f, h, j). Data are means ± s.e.m. from biological replicates.
Extended Data Fig. 4 MCT1 is efficiently deleted in Treg cells of Slc16a1f/fFoxp3YFP-Cre mice and is not required for function of peripheral Treg cells.
a, Slc16a1 expression in Tconv and Treg cells from the LN of Foxp3Cre or Slc16a1f/fFoxp3Cre mice, showing the relative fold change with respect to Foxp3Cre Tconv cells. b, Expression of Slc16a3 (MCT4) mRNA in Treg cells from mice as in a. c, d, Production of CD44, Ki67 and IFNγ by LN CD8+ T cells (c, *P = 0.039) or Tconv cells (d, **P = 0.007) from mice as in a. e, Capacity of LN-derived Treg cells as in a to suppress proliferation of CTV-labelled Tconv cells. f, Percentage of Foxp3+ and Nrp1+Helios+ LN Treg cells from mice as in a. *P = 0.013. g, Expression of CD44, Ki67 and CD62L by LN Treg cells as in a. h, Expression of CD39 and CD73 by LN Treg cells as in a. i, j, Percentage of Foxp3+ cells (i) or GlucoseCy5+ Treg cells (j) from various tissues of mice as in a. Thymus, *P = 0.014; B16, *P = 0.019. k, Normalized ear thickness of imiquimod-treated mice as in a. l, Percentage of marker-positive Treg cells from mice treated as in k. m, Expression of Foxp3 in transferred wild-type or Slc16a1-deficient Treg cells infused with Thy1.1+ Tconv cells into Rag1–/– mice intravenously. *P = 0.02. n, Weight of Rag1–/– mice from m over time. o, Representative sections of the colon and quantified histology scores seven weeks after cell transfer from mice in m and Fig. 2d. **P = 0.001; **P = 0.009. p, Anti-pimonidazole area over total tumour (B16) area, calculated from immunofluorescence from Foxp3Cre and Slc16a1f/fFoxp3Cre mice. q, IL-2 and IFNγ expression by Slc16a1-deficient Tconv cells stimulated overnight with PMA/ionomycin. Results are representative of four (c, d, f, g), three (a, b, e, h, j, p, q) or two (k, l, m, i, o) independent experiments. Significance (*P < 0.05; **P < 0.01; ****P < 0.0001) was determined by unpaired two-tailed t-test (a–d, f–q) or two-way ANOVA (e). Data are means ± s.e.m. from biological replicates.
Extended Data Fig. 5 Acute deletion of MCT1 results in immunological phenotypes similar to those produced by constitutive deletion and predilection for a fragile Treg phenotype.
a, Foxp3Cre-ERT2 and Slc16a1f/fFoxp3Cre-ERT2 mice were given five consecutive doses (on days –4 to 0) of tamoxifen intraperitoneally before being inoculated with 1.5 × 105 B16 tumour cells intradermally (on day 0). Following inoculation, tamoxifen was administered intraperitoneally 3 times a week until animals were killed at day 14. b, Percentage of Foxp3+ CD4+ cells in the LN and TILs as in a. **P = 0.005. c, IFNγ production by Treg cells from the LN and TILs of mice as in a. **P = 0.002. d, Glucose consumption by Treg cells from the TIL of mice as in a. e, Percentage of proliferating (Ki67+) Tconv cells from the TIL of mice as in a. *P = 0.037. f, Representative flow plot and charts showing IFNγ and TNF production by CD8+ T cells from the TIL of mice as in a. **P = 0.003; *P = 0.02. Also shown is IFNγ production by Tconv cells from the TIL of mice as in a. **P = 0.003. g, Mean fluorescence intensity of Nrp1 on intratumoral Treg cells derived from MEER bearing Foxp3Cre-ERT2 and Slc16a1f/fFoxp3Cre-ERT2 mice treated as in a. *P = 0.034. h, Tim-3 expression by MEER-derived CD8+ T cells from mice as in g. **P = 0.003. Results are representative of four (b–e), or three (f) or two (g, h) independent experiments. Significance (*P < 0.05; **P < 0.01) was determined by unpaired two-tailed t-test (b–h). Data are means ± s.e.m. from biological replicates.
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Watson, M.J., Vignali, P.D.A., Mullett, S.J. et al. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature 591, 645–651 (2021). https://doi.org/10.1038/s41586-020-03045-2
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DOI: https://doi.org/10.1038/s41586-020-03045-2
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