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Up-regulation of Inhibitory Natural Killer Receptors CD94/NKG2A with Suppressed Intracellular Perforin Expression of Tumor-Infiltrating CD8⁺ T Lymphocytes in Human Cervical Carcinoma

Departments of ¹ Obstetrics and Gynecology and ² Pathology, National Taiwan University Hospital and ³ Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan

Requests for reprints: Hong-Nerng Ho or Su-Cheng Huang, Department of Obstetrics and Gynecology, National Taiwan University Hospital, No.7 Chung-Shan South Road, Taipei, 100, Taiwan. Phone: 886-2-2364-8233; Fax: 886-2-2709-2570; E-mail: bcsheu{at}ha.mc.ntu.edu.tw.

Inhibitory signals that govern the cytolytic functions of CD8⁺ T lymphocytes have been linked to the expression of natural killer cell receptors (NKRs) on CTLs. There is limited knowledge about the induction of inhibitory NKR (iNKR) expression in vivo. Up-regulation of iNKRs has been linked to the modulation of the virus- and/or tumor-specific immune responses in animal models. In the present study, we directly examined the expression of various NKRs on tumor-infiltrating lymphocytes (TILs) derived from human cervical cancer. We found that in human cervical cancer, the percentage expression of immunoglobulin-like NKR⁺CD8⁺ T lymphocytes were similar in gated CD8⁺-autologous TILs and peripheral blood mononuclear cells. On the contrary, cervical cancer–infiltrating CD8⁺ T lymphocytes expressed up-regulated C-type lectin NKRs CD94/NKG2A compared with either peripheral blood CD8⁺ T cells or normal cervix-infiltrating CD8⁺ T lymphocytes. Dual NKR coexpression analyses showed that CD94 and NKG2A were mainly expressed on CD56^–CD161^–CD8⁺ TILs within the cancer milieu. Immunohistochemical study showed that cervical cancer cells expressed abundant interleukin 15 (IL-15) and transforming growth factor-ß (TGF-ß). In kinetic coculture assay, cervical cancer cells can promote the expression of CD94/NKG2A on CD8⁺ T lymphocytes. The cancer-derived effects can be reversed by addition of rIL-15R/Fc and anti–TGF-ß antibody. Functional analyses illustrated that intracellular perforin expression of CD8⁺ T cells was minimal upon up-regulation of CD94/NKG2A. Kinetic cytotoxicity assays showed that up-regulated expressions of CD94/NKG2A restrain CD8⁺ T lymphocyte cytotoxicity. Our study strongly indicated that cervical cancer cells could promote the expression of iNKRs via an IL-15– and possibly TGF-ß–mediated mechanism and abrogate the antitumor cytotoxicity of TILs.

Key Words: human • T lymphocyte • NK receptor • tumor immunology • perforin

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