Up-regulation of inhibitory natural killer receptors CD94/NKG2A with suppressed intracellular perforin expression of tumor-infiltrating CD8 
                        +
                         T lymphocytes in human cervical carcinoma

Bor Ching Sheu; Shin Heng Chiou; Ho Hsiung Lin; Song Nan Chow; Su Cheng Huang; Hong Nerng Ho; Su Ming Hsu

doi:10.1158/0008-5472.CAN-04-2108

Up-regulation of inhibitory natural killer receptors CD94/NKG2A with suppressed intracellular perforin expression of tumor-infiltrating CD8 ⁺ T lymphocytes in human cervical carcinoma

Bor Ching Sheu, Shin Heng Chiou, Ho Hsiung Lin, Song Nan Chow, Su Cheng Huang, Hong Nerng Ho, Su Ming Hsu

Research output: Contribution to journal › Article › peer-review

105 Citations (Scopus)

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-β (TGF-β). 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-15Rα/Fc and anti-TGF-β 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-β-mediated mechanism and abrogate the antitumor cytotoxicity of TILs.

Original language	English
Pages (from-to)	2921-2929
Number of pages	9
Journal	Cancer Research
Volume	65
Issue number	7
DOIs	https://doi.org/10.1158/0008-5472.CAN-04-2108
Publication status	Published - Apr 1 2005
Externally published	Yes

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1158/0008-5472.CAN-04-2108

Cite this

Sheu, B. C., Chiou, S. H., Lin, H. H., Chow, S. N., Huang, S. C., Ho, H. N., & Hsu, S. M. (2005). Up-regulation of inhibitory natural killer receptors CD94/NKG2A with suppressed intracellular perforin expression of tumor-infiltrating CD8 ⁺ T lymphocytes in human cervical carcinoma. Cancer Research, 65(7), 2921-2929. https://doi.org/10.1158/0008-5472.CAN-04-2108

Up-regulation of inhibitory natural killer receptors CD94/NKG2A with suppressed intracellular perforin expression of tumor-infiltrating CD8 ⁺ T lymphocytes in human cervical carcinoma. / Sheu, Bor Ching; Chiou, Shin Heng; Lin, Ho Hsiung et al.
In: Cancer Research, Vol. 65, No. 7, 01.04.2005, p. 2921-2929.

Research output: Contribution to journal › Article › peer-review

Sheu, BC, Chiou, SH, Lin, HH, Chow, SN, Huang, SC, Ho, HN & Hsu, SM 2005, 'Up-regulation of inhibitory natural killer receptors CD94/NKG2A with suppressed intracellular perforin expression of tumor-infiltrating CD8 ⁺ T lymphocytes in human cervical carcinoma', Cancer Research, vol. 65, no. 7, pp. 2921-2929. https://doi.org/10.1158/0008-5472.CAN-04-2108

Sheu BC, Chiou SH, Lin HH, Chow SN, Huang SC, Ho HN et al. Up-regulation of inhibitory natural killer receptors CD94/NKG2A with suppressed intracellular perforin expression of tumor-infiltrating CD8 ⁺ T lymphocytes in human cervical carcinoma. Cancer Research. 2005 Apr 1;65(7):2921-2929. doi: 10.1158/0008-5472.CAN-04-2108

@article{b38e3a86e403445290b0092919d09c90,

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-β (TGF-β). 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-15Rα/Fc and anti-TGF-β 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-β-mediated mechanism and abrogate the antitumor cytotoxicity of TILs.",

author = "Sheu, {Bor Ching} and Chiou, {Shin Heng} and Lin, {Ho Hsiung} and Chow, {Song Nan} and Huang, {Su Cheng} and Ho, {Hong Nerng} and Hsu, {Su Ming}",

year = "2005",

month = apr,

day = "1",

doi = "10.1158/0008-5472.CAN-04-2108",

language = "English",

volume = "65",

pages = "2921--2929",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "7",

}

TY - JOUR

T1 - Up-regulation of inhibitory natural killer receptors CD94/NKG2A with suppressed intracellular perforin expression of tumor-infiltrating CD8 + T lymphocytes in human cervical carcinoma

AU - Sheu, Bor Ching

AU - Chiou, Shin Heng

AU - Lin, Ho Hsiung

AU - Chow, Song Nan

AU - Huang, Su Cheng

AU - Ho, Hong Nerng

AU - Hsu, Su Ming

PY - 2005/4/1

Y1 - 2005/4/1

N2 - 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-β (TGF-β). 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-15Rα/Fc and anti-TGF-β 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-β-mediated mechanism and abrogate the antitumor cytotoxicity of TILs.

AB - 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-β (TGF-β). 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-15Rα/Fc and anti-TGF-β 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-β-mediated mechanism and abrogate the antitumor cytotoxicity of TILs.

UR - http://www.scopus.com/inward/record.url?scp=16844368435&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=16844368435&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-04-2108

DO - 10.1158/0008-5472.CAN-04-2108

M3 - Article

C2 - 15805295

AN - SCOPUS:16844368435

SN - 0008-5472

VL - 65

SP - 2921

EP - 2929

JO - Cancer Research

JF - Cancer Research

IS - 7

ER -