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ATF4-SLC7A11-GSH axis mediates the acquisition of immunosuppressive properties by activated CD4+ T cells in low arginine condition

ABSTRACT: The tumor microenvironment (TME) is restricted in metabolic nutrients including the semi-essential amino acid arginine. While complete arginine deprivation causes T cell dysfunction, it remains unclear how arginine levels fluctuate in the TME to shape T cell fates. Here, we found that the 20μM low arginine condition, as present in multiple TMEs, confers upon activated T cells Treg-like immunosuppressive capacities. In vivo mouse tumor models and human scRNA-Seq datasets reveal positive correlations between low arginine condition and intratumoral Treg accumulation. Mechanistically, low-arginine activated T cells engage in metabolic and transcriptional reprogramming, using the ATF4-SLC7A11-GSH axis, to preserve their suppressive function. These findings improve our understanding of the role of arginine in human T cell biology with potential applications for immunotherapy strategies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE256171 | GEO | 2024/02/25

REPOSITORIES: GEO

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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.

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ATF4-SLC7A11-GSH axis mediates the acquisition of immunosuppressive properties by activated CD4+ T cells in low arginine condition

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