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Decreased NKG2D Expression on CD8⁺ T Cell Is Involved in Immune Evasion in Patients with Gastric Cancer

Authors' Affiliation: Department of Surgery, Division of Surgical Oncology, Tottori University School of Medicine, Yonago, Japan

Requests for reprints: Hiroaki Saito, Department of Surgery, Division of Surgical Oncology, Tottori University School of Medicine, 36-1 Nishi-cho, Yonago 683-8504, Japan. Phone: 81-859-38-6567; Fax: 81-859-38-6569; E-mail: sai10{at}grape.med.tottori-u.ac.jp.

Purpose: Some studies suggest that the immunoreceptor NKG2D expression on CD8⁺ T cells is down-regulated and this reduction may be involved in immune evasion in cancer patients. The present study was designed to investigate NKG2D expression on CD8⁺ T lymphocytes and its relationship to immune evasion in gastric cancer patients.

Experimental Design: NKG2D expression on both circulating and tumor-infiltrating CD8⁺ T cells was evaluated by multicolor flow cytometry. Soluble MHC class I chain-related gene A (MICA) in the sera was quantitated by ELISA. Transwell experiments were carried out to determine the effect of cancer cells on NKG2D expression.

Results: NKG2D expression on circulating CD8⁺ T cells was down-regulated and significantly correlated with IFN- production in gastric cancer patients (r = 0.68; P = 0.007). NKG2D expression was closely related to undifferentiated cancer (P = 0.021) as was the depth of invasion (P = 0.012). There was no difference in soluble MICA between gastric cancer patients and normal controls. NKG2D expression on CD8⁺ T cells was remarkably reduced in the tissue of gastric cancer compared with peripheral blood (P = 0.046). Complete removal of tumor by surgery restored NKG2D expression on CD8⁺ T cells (P = 0.0049). Transwell experiments showed that this down-regulation was induced by direct contact between cancer cells and CD8⁺ T cells and that soluble factors did not affect the NKG2D expression. This phenomenon was blocked by the addition of anti-MICA antibodies.

Conclusions: Decreased NKG2D expression may be one of the key mechanisms responsible for immune evasion by tumors in gastric cancer.

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