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Lactic acid in tumor microenvironments causes dysfunction of NKT cells by interfering with mTOR signaling

Di Xie1,2, Shasha Zhu1,2, Li Bai3,4

  • 1CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Science, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, 230027, China.

Science China. Life Sciences
|December 21, 2016
PubMed

Insights

Tumor acidity impairs NKT cell function by altering their metabolism. Low pH inhibits key signaling pathways, reducing the production of crucial immune-signaling molecules like IFNγ.

Area of Science:

  • Immunology
  • Cellular Metabolism
  • Cancer Biology

Background:

  • Cellular metabolism critically influences immune cell differentiation and function.
  • Tumor microenvironments significantly alter immune cell phenotypes and functions.
  • Natural Killer T (NKT) cells are promising candidates for cancer immunotherapy, but their function within tumor microenvironments is not fully understood.

Purpose of the Study:

  • To investigate the impact of tumor microenvironments on NKT cell function.
  • To elucidate the mechanisms by which tumor acidity affects NKT cell activity.

Main Methods:

  • Culturing NKT cells in conditions mimicking tumor microenvironments.
  • Assessing cytokine production (IFNγ, IL4) under varying pH levels.
  • Analyzing the effects of extracellular pH on mammalian target of rapamycin (mTOR) signaling and promyelocytic leukemia zinc-finger (PLZF) nuclear translocation.

Main Results:

  • Lactic acid in tumor microenvironments inhibited IFNγ and IL4 production by NKT cells, with a more pronounced effect on IFNγ.
  • Low extracellular pH alone was sufficient to induce NKT cell dysfunction.
  • Low extracellular pH suppressed NKT cell function by inhibiting mTOR signaling and PLZF nuclear translocation.

Conclusions:

  • Tumor-associated acidic microenvironments can impair NKT cell function.
  • Metabolic alterations, specifically low extracellular pH, interfere with NKT cell-mediated anti-tumor immunity.
  • Targeting tumor acidity may enhance the efficacy of NKT cell-based immunotherapies.
Keywords:
IFNγNKT cellPLZFlactic acidmTOR

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