Robert Bosch Hospital, Department of Clinical Chemistry, Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology and Institute of Cell Biology and Immunology, University of Stuttgart, Auerbachstr 112, Stuttgart, Germany.
Cancer Res. 2010 Feb 15;70(4):1314-22. doi: 10.1158/0008-5472.CAN-09-3292. Epub 2010 Feb 9.
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 (TGFbeta) in breast cancer cells may be relevant to the emergence of resistance, not only at the level of cell autonomous effects of TGFbeta 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 TGFbeta 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 infiltrating lymphocytes (TIL) obtained from primary breast cancer biopsies. In allogeneic MLTR, 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 TGFbeta-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 TGFbeta neutralizing antibody. Our findings offer evidence that antiestrogen induces immunosuppression in the tumor microenvironment, through a TGFbeta-dependent mechanism that may contribute to the development of antiestrogen resistance in breast cancer.
抗雌激素药物被广泛用于治疗雌激素受体阳性的乳腺癌，但由于耐药性的发展，复发是常见的。抗雌激素诱导乳腺癌细胞转化生长因子β（TGFβ）的能力可能与耐药性的出现有关，不仅与 TGFβ对癌症进展的细胞自主效应有关，而且与它对宿主免疫系统的影响有关。为了评估肿瘤衍生的、抗雌激素诱导的 TGFβ作为免疫抑制剂的潜在作用，我们使用 MCF-7 细胞和外周血单核细胞（PBMC），以及从原发性乳腺癌活检中获得的肿瘤组织和自体肿瘤浸润淋巴细胞（TIL），建立了体外混合淋巴细胞肿瘤反应（MLTR）。在同种异体 MLTR 中，抗雌激素处理的 MCF-7 细胞导致 CD8+T 细胞中效应分子颗粒酶 B、穿孔素和 Fas 配体的下调，并以 TGFβ依赖的方式抑制细胞毒性效应细胞的产生。此外，我们根据 Foxp3 表达和共培养中的 T 细胞活化，在 CD4+T 细胞中记录到调节性 T 细胞的诱导。在自体 MLTR 中，抗雌激素治疗导致 TIL/PBMC 的 Foxp3 表达增强，凋亡肿瘤细胞数量减少。这些作用可被 TGFβ中和抗体逆转。我们的研究结果提供了证据，表明抗雌激素通过 TGFβ依赖性机制在肿瘤微环境中诱导免疫抑制，这可能有助于乳腺癌中抗雌激素耐药性的发展。
