Dataset Information

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

ABSTRACT: Regulatory T (T_reg) 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 cells^1,2. 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 function^4-6. At the same time, T_reg cells maintain a strong suppression of effector T cells within the TME^7,8. As previous studies suggested that T_reg cells possess a distinct metabolic profile from effector T cells^9-11, we hypothesized that the altered metabolic landscape of the TME and increased activity of intratumoral T_reg cells are linked. Here we show that T_reg 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 T_reg cells in vitro. T_reg cells instead upregulate pathways involved in the metabolism of the glycolytic by-product lactic acid. T_reg 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 T_reg cells reveals that lactate uptake is dispensable for the function of peripheral T_reg cells but required intratumorally, resulting in slowed tumour growth and an increased response to immunotherapy. Thus, T_reg 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.

SUBMITTER: Watson MJ

PROVIDER: S-EPMC7990682 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Regulatory T (Treg) cells are vital for maintaining immune homeostasis and preventing autoimmunity, but represent a major barrier to robust cancer immunity as the tumor microenvironment (TME) actively recruits, activates, and promotes their differentiation1,2. Tumor cells have deregulated cellular metabolism leading to a metabolite-depleted, hypoxic, and acidic TME3. Highly glycolytic tumor infiltrating CD8 T cells are in direct competition with the tumor for glucose and oxygen which impairs their effector function4–6. In contrast, Treg cells maintain their high suppressive function within the TME7,8. Further, studies of in vitro induced and directly ex vivo Treg cells reveal a distinct metabolic profile compared to effector T cells9–11. Thus, we hypothesized that the altered metabolic landscape of the TME and the increased activity of intratumoral Treg cells are linked. Here we show Treg cells display heterogeneity in terms of their glucose metabolism and can engage an alternative metabolic pathway to maintain their high suppressive function and proliferation within the TME and other tissues. Tissue derived Treg cells (both at the steady state and under inflammatory conditions) show broad heterogeneity in their ability to take up glucose. However, glucose uptake correlates with poorer suppressive function and long-term functional stability, and culture of Treg cells in high glucose conditions decreased suppressive function. Treg cells under low glucose conditions upregulate genes associated with the uptake and metabolism of the glycolytic end-product lactic acid. Treg cells withstand high lactate conditions, and lactate treatment prevents the destabilizing effects of high glucose culture. Treg cells utilize lactate within the TCA cycle and generate phosphoenolpyruvate (PEP), a critical intermediate that can fuel intratumoral Treg cell proliferation in vivo. Using mice with a Treg cell-restricted deletion of lactate transporter Slc16a1 (MCT1) we show MCT1 is dispensable for peripheral Treg cell function but required intratumorally, resulting in slowed tumor growth and prolonged survival. These data support a model in which Treg cells are metabolically flexible such that they can utilize ‘alternative’ metabolites present in the TME to maintain their suppressive identity. Further, our studies support the notion that tumors avoid immune destruction not only by depriving effector T cells of essential nutrients, but also by metabolically supporting regulatory T cells.

Project description:Inflammatory mechanisms influence tumorigenesis and metastatic progression even in cancers whose aetiology does not involve pre-existing inflammation or infection, such as breast and prostate cancers. For instance, prostate cancer metastasis is associated with the infiltration of lymphocytes into advanced tumours and the upregulation of two tumour-necrosis-factor family members: receptor activator of nuclear factor-?B (RANK) ligand (RANKL) and lymphotoxin. But the source of RANKL and its role in metastasis have not been established. RANKL and its receptor RANK control the proliferation of mammary lobuloalveolar cells during pregnancy through inhibitor of nuclear factor-?B (I?B) kinase-? (IKK-?), a protein kinase that is needed for the self-renewal of mammary cancer progenitors and for prostate cancer metastasis. We therefore examined whether RANKL, RANK and IKK-? are also involved in mammary/breast cancer metastasis. Indeed, RANK signalling in mammary carcinoma cells that overexpress the proto-oncogene Erbb2 (also known as Neu), which is frequently amplified in metastatic human breast cancers, was important for pulmonary metastasis. Metastatic spread of Erbb2-transformed carcinoma cells also required CD4(+)CD25(+) T cells, whose major pro-metastatic function was RANKL production. Most RANKL-producing T cells expressed forkhead box P3 (FOXP3), a transcription factor produced by regulatory T cells, and were located next to smooth muscle actin (SMA)(+) stromal cells in mouse and human breast cancers. The dependence of pulmonary metastasis on T cells was replaceable by exogenous RANKL, which also stimulated pulmonary metastasis of RANK(+) human breast cancer cells. These results are consistent with the adverse impact of tumour-infiltrating CD4(+) or FOXP3(+) T cells on human breast cancer prognosis and suggest that the targeting of RANKL-RANK can be used in conjunction with the therapeutic elimination of primary breast tumours to prevent recurrent metastatic disease.

Dataset Information

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets