Antiestrogens are universally used to treat estrogen receptor–positive breast cancer, but relapses occur commonly due to the development of drug resistance. The ability of antiestrogen to induce transforming growth factor $\beta$ (TGF$\beta$) in breast cancer cells may be relevant to the emergence of resistance, not only at the level of cell autonomous effects of TGF$\beta$ on cancer progression but also at the level of its effects on the host immune system. To evaluate the potential role of tumor-derived, antiestrogen-induced TGF$\beta$ as an immune suppressor, we established in vitro mixed lymphocyte tumor reactions (MLTR) using MCF-7 cells and peripheral blood mononuclear cells (PBMC), as well as tumor tissue and autologous tumor in- filtrating lymphocytes (TIL) obtained from primary breast cancer biopsies. In allogeneicMLTR, antiestrogen- treated MCF-7 cells caused downregulation of the effector molecules granzyme B, perforin, and Fas ligand in CD8+ T cells, and suppressed the generation of cytotoxic effector cells in a TGF$\beta$-dependent manner. Furthermore, we documented induction of regulatory T cells in CD4+ T cells, based on Foxp3 expression and T-cell activation in cocultures. In autologous MLTR, antiestrogen treatment gave rise to enhanced Foxp3 expression of TIL/PBMC and decreased the number of apoptotic tumor cells. These effects were reversed by addition of a TGF$\beta$ neutralizing antibody. Our findings offer evidence that antiestrogen in- duces immunosuppression in the tumor microenvironment, through a TGF$\beta$-dependent mechanism that may contribute to the development of antiestrogen resistance in breast cancer.
%0 Journal Article
%1 Joffroy2010
%A Joffroy, Christian M.
%A Buck, Miriam B.
%A Stope, Matthias B.
%A Popp, Simone L.
%A Pfizenmaier, Klaus
%A Knabbe, Cornelius
%D 2010
%J Cancer Research
%K 2010 izi pfizenmaier
%N 4
%P 1314--1322
%R 10.1158/0008-5472.CAN-09-3292
%T Antiestrogens induce transforming growth factor $\beta$-mediated immunosuppression in breast cancer
%U https://www.ncbi.nlm.nih.gov/pubmed/20145137
%V 70
%X Antiestrogens are universally used to treat estrogen receptor–positive breast cancer, but relapses occur commonly due to the development of drug resistance. The ability of antiestrogen to induce transforming growth factor $\beta$ (TGF$\beta$) in breast cancer cells may be relevant to the emergence of resistance, not only at the level of cell autonomous effects of TGF$\beta$ on cancer progression but also at the level of its effects on the host immune system. To evaluate the potential role of tumor-derived, antiestrogen-induced TGF$\beta$ as an immune suppressor, we established in vitro mixed lymphocyte tumor reactions (MLTR) using MCF-7 cells and peripheral blood mononuclear cells (PBMC), as well as tumor tissue and autologous tumor in- filtrating lymphocytes (TIL) obtained from primary breast cancer biopsies. In allogeneicMLTR, antiestrogen- treated MCF-7 cells caused downregulation of the effector molecules granzyme B, perforin, and Fas ligand in CD8+ T cells, and suppressed the generation of cytotoxic effector cells in a TGF$\beta$-dependent manner. Furthermore, we documented induction of regulatory T cells in CD4+ T cells, based on Foxp3 expression and T-cell activation in cocultures. In autologous MLTR, antiestrogen treatment gave rise to enhanced Foxp3 expression of TIL/PBMC and decreased the number of apoptotic tumor cells. These effects were reversed by addition of a TGF$\beta$ neutralizing antibody. Our findings offer evidence that antiestrogen in- duces immunosuppression in the tumor microenvironment, through a TGF$\beta$-dependent mechanism that may contribute to the development of antiestrogen resistance in breast cancer.
%Z Joffroy, Christian MBuck, Miriam BStope, Matthias BPopp, Simone LPfizenmaier, KlausKnabbe, CorneliusengResearch Support, Non-U.S. Gov'tCancer Res. 2010 Feb 15;70(4):1314-22. doi: 10.1158/0008-5472.CAN-09-3292. Epub 2010 Feb 9.
%7 2010/02/11
%@ 1538-7445 (Electronic)
0008-5472 (Linking)
@article{Joffroy2010,
abstract = {Antiestrogens are universally used to treat estrogen receptor–positive breast cancer, but relapses occur commonly due to the development of drug resistance. The ability of antiestrogen to induce transforming growth factor $\beta$ (TGF$\beta$) in breast cancer cells may be relevant to the emergence of resistance, not only at the level of cell autonomous effects of TGF$\beta$ on cancer progression but also at the level of its effects on the host immune system. To evaluate the potential role of tumor-derived, antiestrogen-induced TGF$\beta$ as an immune suppressor, we established in vitro mixed lymphocyte tumor reactions (MLTR) using MCF-7 cells and peripheral blood mononuclear cells (PBMC), as well as tumor tissue and autologous tumor in- filtrating lymphocytes (TIL) obtained from primary breast cancer biopsies. In allogeneicMLTR, antiestrogen- treated MCF-7 cells caused downregulation of the effector molecules granzyme B, perforin, and Fas ligand in CD8+ T cells, and suppressed the generation of cytotoxic effector cells in a TGF$\beta$-dependent manner. Furthermore, we documented induction of regulatory T cells in CD4+ T cells, based on Foxp3 expression and T-cell activation in cocultures. In autologous MLTR, antiestrogen treatment gave rise to enhanced Foxp3 expression of TIL/PBMC and decreased the number of apoptotic tumor cells. These effects were reversed by addition of a TGF$\beta$ neutralizing antibody. Our findings offer evidence that antiestrogen in- duces immunosuppression in the tumor microenvironment, through a TGF$\beta$-dependent mechanism that may contribute to the development of antiestrogen resistance in breast cancer.},
added-at = {2023-06-29T13:07:55.000+0200},
annote = {Joffroy, Christian MBuck, Miriam BStope, Matthias BPopp, Simone LPfizenmaier, KlausKnabbe, CorneliusengResearch Support, Non-U.S. Gov'tCancer Res. 2010 Feb 15;70(4):1314-22. doi: 10.1158/0008-5472.CAN-09-3292. Epub 2010 Feb 9.},
author = {Joffroy, Christian M. and Buck, Miriam B. and Stope, Matthias B. and Popp, Simone L. and Pfizenmaier, Klaus and Knabbe, Cornelius},
biburl = {https://puma.ub.uni-stuttgart.de/bibtex/2b106733e6881c0cd4f32997bd20958ee/fabian},
doi = {10.1158/0008-5472.CAN-09-3292},
edition = {2010/02/11},
interhash = {e801a1b1767b2cd49ba603fa5897827b},
intrahash = {b106733e6881c0cd4f32997bd20958ee},
isbn = {1538-7445 (Electronic)
0008-5472 (Linking)},
issn = {00085472},
journal = {Cancer Research},
keywords = {2010 izi pfizenmaier},
number = 4,
pages = {1314--1322},
pmid = {20145137},
timestamp = {2023-06-29T13:07:55.000+0200},
title = {{Antiestrogens induce transforming growth factor $\beta$-mediated immunosuppression in breast cancer}},
url = {https://www.ncbi.nlm.nih.gov/pubmed/20145137},
volume = 70,
year = 2010
}