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

Di Xie,Li Bai,Shasha Zhu

doi:10.1007/s11427-016-0348-7

Abstract

Cellular metabolism has been shown to regulate differentiation and function of immune cells. Tumor associated immune cells undergo phenotypic and functional alterations due to the change of cellular metabolism in tumor microenvironments. NKT cells are good candidates for immunotherapies against tumors and have been used in several clinical trials. However, the influences of tumor microenvironments on NKT cell functions remain unclear. In our studies, lactic acid in tumor microenvironments inhibited IFNγ and IL4 productions from NKT cells, and more profound influence on IFNγ was observed. By adjusting the pH of culture medium we further showed that, dysfunction of NKT cells could simply be induced by low extracellular pH. Moreover, low extracellular pH inhibited NKT cell functions by inhibiting mammalian target of rapamycin (mTOR) signaling and nuclear translocation of promyelocytic leukemia zinc-finger (PLZF). Together, our results suggest that tumor acidic microenvironments could interfere with NKT cell functions through metabolic controls.

Highlights

NKT cells are CD1d-restricted T lymphocytes, which possess semi-invariant TCR, have effector phenotypes and recognize lipid antigens
To study the influences of tumor microenvironments on NKT cell functions, NKT cells plus RBL.CD1d cells in upper chamber were co-cultured with tumor cells in lower plate in the presence of αGC in transwell systems
Our results indicate a significant influence of tumor microenvironments on NKT cell functions

Summary

Introduction

NKT cells are CD1d-restricted T lymphocytes, which possess semi-invariant TCR, have effector phenotypes and recognize lipid antigens. Transferring in vitro expanded NKT cells or αGC-pulsed DCs showed significant prolonged mean survival time and stabilization of disease (Motohashi et al, 2006; Motohashi et al, 2009; Motohashi et al, 2011). Some of those patients with low IFNγ production showed no clinical effects (Motohashi et al, 2011). Optimal IFNγ production is important for the antitumor effects of NKT cells. Antigens and types of antigen-presenting cells are extrinsic factors modulating the cytokine responses of NKT

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Conclusion