Modulation of bone morphogenic protein signaling in T-cells for cancer immunotherapy.
Modulation of bone morphogenic protein signaling in T-cells for cancer immunotherapy.
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DOI：
10.3109/1547691x.2013.864736
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发表时间：
2014-10
影响因子：
3.3
通讯作者：
Kraj P
中科院分区：
文献类型：
--
作者：
Kuczma M;Kurczewska A;Kraj P
免疫疗法正成为传统癌症疗法越来越有吸引力的治疗替代方案。近年来，Foxp 3+调节性T细胞（TR）被确定为有效癌症免疫治疗的主要障碍。这些细胞在外周血中的丰度在患有多种类型癌症的患者中增加，并且它们在肿瘤浸润淋巴细胞中的流行与不良临床预后相关。相反，TR细胞的去除或失活导致增强的抗肿瘤免疫应答和更好的癌症疫苗功效。我们报道了骨形态发生蛋白受体1α（BMPR 1 α，Alk-3）由活化的效应细胞CD 4+和TR表达，并调节这两种细胞类型的功能。骨形态发生蛋白（BMP）属于细胞因子的转化生长因子（TGF）-β家族，也包括TGFβ和激活素。骨形成蛋白在胚胎发育、组织分化、体内平衡和肿瘤的发生发展中起着至关重要的作用.已证明BMP和激活素与TGFβ协同调节胸腺T细胞发育、维持TR细胞和控制外周耐受。T细胞中BMPR 1 α的失活导致胸腺和外周TR细胞生成受损。BMPR 1 α缺陷的活化T细胞比BMPR 1 α充足的T细胞产生更高水平的干扰素（IFN）-γ。此外，移植的B16黑色素瘤肿瘤在T细胞中缺乏BMPR 1 α表达的小鼠中生长得更小，并且肿瘤具有很少的浸润TR细胞和比野生型小鼠更高比例的CD 8 + T细胞。
Immunotherapy is becoming an increasingly attractive therapeutic alternative for conventional cancer therapy. In recent years Foxp3+ regulatory T-cells (TR) were identified as the major obstacle to effective cancer immunotherapy. The abundance of these cells in peripheral blood is increased in patients with multiple types of cancer and their prevalence among tumor-infiltrating lymphocytes correlated with poor clinical prognosis. In contrast, removal or inactivation of TR cells led to enhanced antitumor immune response and better efficacy of cancer vaccines. We report that Bone Morphogenic Protein Receptor 1α (BMPR1α, Alk-3), is expressed by activated effector CD4+ and TR cells and modulates functions of both cell types. Bone Morphogenic Proteins (BMPs) belong to the transforming growth factor (TGF)-β family of cytokines that also include TGFβ and activins. BMPs play crucial roles in- embryonic development, tissue differentiation and homeostasis and development of cancer. It was demonstrated that BMPs and activins synergize with TGFβ to regulate thymic T-cell development, maintain TR cells and control peripheral tolerance. Inactivation of BMPR1α in T-cells results in impaired thymic and peripheral generation of TR cells. BMPR1α -deficient activated T-cells produced higher level of interferon (IFN)-γ than BMPR1α-sufficient T-cells. Moreover, transplanted B16 melanoma tumors grew smaller in mice lacking expression of BMPR1α in T-cells and tumors had few infiltrating TR cells and a higher proportion of CD8+ T-cells than wild-type mice.