Metabolic advantages of regulatory T cells dictated by cancer cells

Author:

Kondo Masaki123,Kumagai Shogo124,Nishikawa Hiroyoshi125

Affiliation:

1. Division of Cancer Immunology, Research Institute, National Cancer Center , Tokyo 104-0045 , Japan

2. Division of Cancer Immunology, Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center , Chiba 277-8577 , Japan

3. Department of Neurosurgery, Nagoya University Graduate School of Medicine , Nagoya 466 – 8550 , Japan

4. Division of Cellular Signaling, National Cancer Center Research Institute , Tokyo 104-0045 , Japan

5. Department of Immunology, Nagoya University Graduate School of Medicine , Nagoya 466 – 8550 , Japan

Abstract

Abstract Cancer cells employ glycolysis for their survival and growth (the “Warburg effect”). Consequently, surrounding cells including immune cells in the tumor microenvironment (TME) are exposed to hypoglycemic, hypoxic, and low pH circumstances. Since effector T cells depend on the glycolysis for their survival and functions, the metabolically harsh TME established by cancer cells is unfavorable, resulting in the impairment of effective antitumor immune responses. By contrast, immunosuppressive cells such as regulatory T (Treg) cells can infiltrate, proliferate, survive, and exert immunosuppressive functions in the metabolically harsh TME, indicating the different metabolic dependance between effector T cells and Treg cells. Indeed, some metabolites that are harmful for effector T cells can be utilized by Treg cells; lactic acid, a harmful metabolite for effector T cells, is available for Treg cell proliferation and functions. Deficiency of amino acids such as tryptophan and glutamine in the TME impairs effector T cell activation but increases Treg cell populations. Furthermore, hypoxia upregulates fatty acid oxidation via hypoxia-inducible factor 1α (HIF-1α) and promotes Treg cell migration. Adenosine is induced by the ectonucleotidases CD39 and CD73, which are strongly induced by HIF-1α, and reportedly accelerates Treg cell development by upregulating Foxp3 expression in T cells via A2AR-mediated signals. Therefore, this review focuses on the current views of the unique metabolism of Treg cells dictated by cancer cells. In addition, potential cancer combination therapies with immunotherapy and metabolic molecularly targeted reagents that modulate Treg cells in the TME are discussed to develop “immune metabolism-based precision medicine”.

Funder

Grants-in-Aid for Scientific Research

Japan Society for the Promotion of Science

KAKENHI

Ministry of Education, Culture, Sports, Science and Technology of Japan

Moonshot Research and Development Program

Cancer Research by Therapeutic Evolution

Development of Technology for Patient Stratification Biomarker Discovery

Practical Research for Innovative Cancer Control

Japan Agency for Medical Research and Development

National Cancer Center Research and Development Fund

Publisher

Oxford University Press (OUP)

Subject

Immunology,General Medicine,Immunology and Allergy

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