title: Up-regulation of inhibitory natural killer receptors CD94/NKG2A with suppressed intracellular perforin expression of tumor-infiltrating CD8+ T lymphocytes in human cervical carcinoma.
abstract: 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-beta (TGF-beta). 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-15Ralpha/Fc and anti-TGF-beta 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-beta-mediated mechanism and abrogate the antitumor cytotoxicity of TILs.
authors.affiliation: Department of Obstetrics and Gynecology, National Taiwan University Hospital and Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan. bcsheu@ha.mc.ntu.edu.tw
authors.forename: Bor-Ching
authors.initials: BC
authors.lastname: Sheu
authors.forename: Shin-Heng
authors.initials: SH
authors.lastname: Chiou
authors.forename: Ho-Hsiung
authors.initials: HH
authors.lastname: Lin
authors.forename: Song-Nan
authors.initials: SN
authors.lastname: Chow
authors.forename: Su-Cheng
authors.initials: SC
authors.lastname: Huang
authors.forename: Hong-Nerng
authors.initials: HN
authors.lastname: Ho
authors.forename: Su-Ming
authors.initials: SM
authors.lastname: Hsu
mesh_terms: D015703:Antigens, CD / Q000096:biosynthesis* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D005260:Female; D006801:Humans; D019409:Interleukin-15 / Q000494:pharmacology; D037181:Lectins, C-Type / Q000096:biosynthesis* / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000276:immunology; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011971:Receptors, Immunologic / Q000096:biosynthesis* / Q000276:immunology; D055607:Receptors, Natural Killer Cell; D011994:Recombinant Proteins / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D015854:Up-Regulation; D002583:Uterine Cervical Neoplasms / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D019409:Interleukin-15; C527054:KLRC1 protein, human; C497869:KLRD1 protein, human; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D052899:Pore Forming Cytotoxic Proteins; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D054353:Perforin