Analysis of host versus tumor interaction in cancer patients: opposing role of transforming growth factor-beta1 and interleukin-6 in the development of in situ tumor immunity.
A different degree of immunodeficiency is often found at tumor sites in cancer patients. At the late stage many patients develop malignant effusion that contains large numbers of tumor cells and host immune cells that constantly interact with each other. These sites may provide an ideal model to examine in situ anti-tumor immunity. The T cells in effusion were found to be immunodeficient, which suggested a defective anti-tumor cytotoxic T lymphocytes response. To pursue the mechanism for the T cell deficiency, we determined the production of immunomodulating cytokines in the effusion and detected the presence of transforming growth factor-beta1 (TGFbeta), prostaglandin E2, IL-6, IL-10, and IFNgamma. There was no detectable IL-2, IL-4, IL-12, or TNFalpha. The most prominent feature was the presence of TGFbeta and IL-6 at a very high level. Thus, the possible role of these two cytokines on T cell competence was further determined. TGFbeta was found to induce T cell anergy and reduced the production of perforin in T killer cells and their lytic activity. These events lead to the induction of peripheral T cell tolerance with profound T cell deficiency. IL-6 did not affect perforin production or cytolytic activity of the T killer cells. But the CD4+ CD25+ regulatory T cells (TR) that were often employed by TGFbeta to suppress T cell response were reduced in the malignant effusion, consistent with the fact that IL-6 down-regulates TR and this may represent the host's vigorous response to the tumor's subversion. These results show that TGFbeta and IL-6 might play pivotal but opposing roles in the host tumor interaction that, together with other immunomodulating components, determines the outcome for the development of local tumor immunity.
Tsai
Jy-Ping
JP
Immunology Group, National Health Research Institutes, Taipei, Taiwan.
Chen
Hsin-Wei
HW
Cheng
Mei-Lien
ML
Liu
Hsiung-Kun
HK
Lee
Yi-Ping
YP
Hsieh
Chia Ling
CL
Luh
Kwen-Tay
KT
Wu
Chew-Wun
CW
Hsu
Li-Han
LH
Chao
Tsu-Yi
TY
Wang
Wen-Hua
WH
Chang
Chung-Ming
CM
Ting
Chou-Chik
CC
D000328:Adult; D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007121:Immunocompetence; D007165:Immunosuppression Therapy; D015850:Interleukin-6 / Q000378:metabolism*; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
D015850:Interleukin-6; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D054353:Perforin