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01-12-2019 | Original Article

Regulatory T cells induce CD4⁻ NKT cell anergy and suppress NKT cell cytotoxic function

Authors: Fumie Ihara, Daiju Sakurai, Mariko Takami, Toshiko Kamata, Naoki Kunii, Kazuki Yamasaki, Tomohisa Iinuma, Toshinori Nakayama, Shinichiro Motohashi, Yoshitaka Okamoto

Published in: Cancer Immunology, Immunotherapy | Issue 12/2019

Abstract

Background

Due to the strong tumoricidal activities of activated natural killer T (NKT) cells, invariant NKT cell-based immunotherapy has shown promising clinical efficacy. However, suppressive factors, such as regulatory T cells (Tregs), may be obstacles in the use of NKT cell-based cancer immunotherapy for advanced cancer patients. Here, we investigated the suppressive effects of Tregs on NKT cells and the underlying mechanisms with the aim to improve the antitumor activities of NKT cells.

Methods

Peripheral blood samples were obtained from healthy donors, patients with benign tumors, and patients with head and neck squamous cell carcinoma (HNSCC). NKT cells, induced with α-galactosylceramide (α-GalCer), and monocyte-derived dendritic cells (DCs) were co-cultured with naïve CD4⁺ T cell-derived Tregs to investigate the mechanism of the Treg suppressive effect on NKT cell cytotoxic function. The functions and phenotypes of NKT cells were evaluated with flow cytometry and cytometric bead array.

Results

Treg suppression on NKT cell function required cell-to-cell contact and was mediated via impaired DC maturation. NKT cells cultured under Treg-enriched conditions showed a decrease in CD4⁻ NKT cell frequency, which exert strong tumoricidal responsiveness upon α-GalCer stimulation. The same results were observed in HNSCC patients with significantly increased effector Tregs.

Conclusion

Tregs exert suppressive effects on NKT cell tumoricidal function by inducing more CD4⁻ NKT cell anergy and less CD4⁺ NKT cell anergy. Both Treg depletion and NKT cell recovery from the anergy state may be important for improving the clinical efficacy of NKT cell-based immunotherapy in patients with advanced cancers.

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Title: Regulatory T cells induce CD4− NKT cell anergy and suppress NKT cell cytotoxic function
Authors: Fumie Ihara
Daiju Sakurai
Mariko Takami
Toshiko Kamata
Naoki Kunii
Kazuki Yamasaki
Tomohisa Iinuma
Toshinori Nakayama
Shinichiro Motohashi
Yoshitaka Okamoto
Publication date: 01-12-2019
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 12/2019
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-019-02417-6

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