HIF1a-regulated glycolysis promotes activation-induced cell death and IFN-g induction in hypoxic T cells

Most T cells live in hypoxia that shapes their survival and functions (e.g., IFN-g induction). Despite a key role of HIF1a in orchestrating cellular adaptive responses to hypoxia, whether and how HIF1a controls IFN-g induction in hypoxic T cells is elusive, a knowledge gap filled by our study.
Published in Cancer
HIF1a-regulated glycolysis promotes activation-induced cell death and IFN-g induction in hypoxic T cells
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Glycolysis is absolutely required for IFN-g induction in T cells1, 2, 3. Intriguingly, under normoxia, this is not mediated by HIF1a1, a primary regulator of glycolysis, but by its widely regarded downstream target LDHa2. However, it remains unknown, under hypoxia, whether and how HIF1a regulates IFN-g induction in T cells. 

Hypoxia is a common feature in various physiological and pathological settings. Physiologically, other than the tissues directly exposed to inhaled atmospheric air (such as the upper airways), most healthy tissues experience some degree of O2 deprivation. For examples, the O2 tension in the interstitial space of tissues is ~5-6%4. In spleen, it is mostly ~3-4%5 but lowered in the germinal center6. In the gastrointestinal (GI) tract that hosts ~70-80% of the total lymphocytes in our body7, a wide range of O2 tensions exists, being almost anoxic in the lumen and slightly increased at the base of the villi8. Pathologically, the microenvironment of solid tumor9 and the inflammatory sites10 have an oxygen level ~1% O2. Thus, most T cells live under hypoxia. Given the crucial role of HIF1a in orchestrating cellular adaptive responses to hypoxia11 and the pivotal role of IFN-g in immunity against intracellular pathogens and tumors12, it is of utmost importance to understand the role of HIF1a in IFN-g induction in hypoxic T cells.

In this study13, combining genetic mouse models, metabolic flux analysis using 13C-labeled glucose tracing assay and Seahorse analyzer, and pharmacological approaches, we show that HIF1a-glycolysis is indispensable for IFN-g induction in hypoxic T cells. HIF1a deletion and glycolytic inhibition drastically reduces IFN-g induction, whereas HIF1a stabilization greatly augments IFN-g production. The HIF1a-glycolysis axis, by sustaining intracellular acetyl-CoA and activation-induced cell death (AICD), governs T cell effector functions and responses to immune checkpoint blockade (ICB). Acetate supplementation, by restoring the intracellular acetyl CoA as well as H3K9Ac expression in the promoter and regulatory regions of Ifng gene in Hif1a KO T cells, enhances Ifng transcription and rescues IFN-g production and tumor-killing capacity of Hif1a KO T cells; it also resensitizes Hif1a KO mice bearing tumors to ICB therapies.

Based on this study, several lines of investigation would be worth pursuing: 1. Our data establish HIF1a as a key mediator of activation-induced metabolic reprogramming in hypoxic T cells, paralleling to the essential role of Myc in normoxic T cells14. It would be interesting to investigate whether Myc also plays a role in hypoxic T cells and if so, how HIF1a interacts with Myc to achieve a delicate control of this complicated metabolic reprogramming. 2. Although attenuated glycolysis in hypoxic Hif1a KO T cells leads to impaired AICD as well as defective cell proliferation, it is the impaired AICD but not proliferation defect in Hif1a KO T cells that underpins the reduced IFN-g induction. Considering the essential role of cell death in the development of thymocytes15, it would be interesting to perform in-depth studies on whether HIF1a may regulate the thymus development. 3. ICBs have induced unprecedented clinical successes in various types of late-stage cancer. But therapeutic resistance to ICBs has becoming a pressing issue. Our study, together with an early report16, compellingly show that the impaired HIF1a function in T cells is a major T cell-intrinsic mechanism of therapeutic resistance to ICBs, like anti-CTLA-4 and anti-PD-1/L1. Future endeavors should focus on defining the crosstalk of T cell HIF1a pathway to tumor-intrinsic mechanisms of ICB resistance, including but not limited to pTEN loss17, loss of the IFN-g signaling18, 19, 20, overactive PI3K21.

In conclusion, we show that HIF1a, by maintaining glycolysis and intracellular acetyl-CoA in activated hypoxic T cells, is required for IFN-g induction and ICB responses (see below Figure).

References

  1. Shi LZ, et al. HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 208, 1367-1376 (2011).
  2. Peng M, Yin N, Chhangawala S, Xu K, Leslie CS, Li MO. Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 354, 481-484 (2016).
  3. Michalek RD, et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol 186, 3299-3303 (2011).
  4. Habler OP, Messmer KF. The physiology of oxygen transport. Transfus Sci 18, 425-435 (1997).
  5. Caldwell CC, et al. Differential effects of physiologically relevant hypoxic conditions on T lymphocyte development and effector functions. J Immunol 167, 6140-6149 (2001).
  6. Cho SH, et al. Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system. Nature 537, 234-238 (2016).
  7. Brandtzaeg P, et al. Immunobiology and immunopathology of human gut mucosa: humoral immunity and intraepithelial lymphocytes. Gastroenterology 97, 1562-1584 (1989).
  8. Karhausen J, Furuta GT, Tomaszewski JE, Johnson RS, Colgan SP, Haase VH. Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis. J Clin Invest 114, 1098-1106 (2004).
  9. Palazon A, et al. The HIF-1alpha hypoxia response in tumor-infiltrating T lymphocytes induces functional CD137 (4-1BB) for immunotherapy. Cancer discovery 2, 608-623 (2012).
  10. Colgan SP, Taylor CT. Hypoxia: an alarm signal during intestinal inflammation. Nat Rev Gastroenterol Hepatol 7, 281-287 (2010).
  11. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3, 721-732 (2003).
  12. Zhu J, Paul WE. CD4 T cells: fates, functions, and faults. Blood 112, 1557-1569 (2008).
  13. Shen H, et al. HIF1α-regulated glycolysis promotes activation-induced cell death and IFN-g induction in hypoxic T cells. Nat Commun 15, 9394 (2024).
  14. Wang R, et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35, 871-882 (2011).
  15. Shi LZ, et al. Gfi1-Foxo1 axis controls the fidelity of effector gene expression and developmental maturation of thymocytes. Proc Natl Acad Sci U S A 114, E67-E74 (2017).
  16. Palazon A, et al. An HIF-1alpha/VEGF-A Axis in Cytotoxic T Cells Regulates Tumor Progression. Cancer cell 32, 669-683 e665 (2017).
  17. Peng W, et al. Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy. Cancer discovery 6, 202-216 (2016).
  18. Gao J, et al. Loss of IFN-gamma Pathway Genes in Tumor Cells as a Mechanism of Resistance to Anti-CTLA-4 Therapy. Cell 167, 397-404 e399 (2016).
  19. Zaretsky JM, et al. Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma. The New England journal of medicine 375, 819-829 (2016).
  20. Shen H, et al. Selective suppression of melanoma lacking IFN-g pathway by JAK inhibition depends on T cells and host TNF signaling. Nat Commun 13, 5013 (2022).
  21. Okkenhaug K, Graupera M, Vanhaesebroeck B. Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy. Cancer discovery 6, 1090-1105 (2016).

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Go to the profile of Lewis Zhichang Shi
24 days ago

I woud lik to share our most recently published story with the research community, wherein we report an indispensable role of HIF1a in driving IFN-g induction in hypoxic T cells and anti-tumor immunity elicited by immune checkpoint blockade therapies. 

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Tumour Immunology
Life Sciences > Biological Sciences > Cancer Biology > Tumour Immunology

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