Deletion of TGF-β signaling in myeloid cells enhances their anti-tumorigenic properties
Deletion of TGF-β signaling in myeloid cells enhances their anti-tumorigenic properties
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DOI：
10.1189/jlb.1211639
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发表时间：
2012-09-01
影响因子：
5.5
通讯作者：
Moses, Harold L.
中科院分区：
文献类型：
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作者：
Novitskiy, Sergey V.;Pickup, Michael W.;Moses, Harold L.
通过与LysM-Cre和转化生长因子-β2型受体(TGFBR2)杂交，我们实现了TGFBR2在髓系细胞(TGFBR2(Myeko)小鼠)中的特异性缺失。皮下注射(LLC，EL4-OVA)和种植(MMTV-PyMT)的癌细胞在TGFBR2(Myeko)小鼠中生长较慢。两种基因型小鼠肿瘤组织中CD45(+)细胞的数量相同，但经分析，KO小鼠T细胞(CD45(+)CD3(+))的百分比增加。通过流式细胞仪分析，TGFBR2(Myeko)和TGFBR2(MyeWT)小鼠在TAMs、CD11b(+)、Gr1(+)和DC的数量和表型上没有发现任何差异。酶联免疫吸附试验和定量逆转录聚合酶链式反应结果显示髓系细胞功能不同。在TGFBR2(Myeko)TAMs中，肿瘤坏死因子-α分泌增加，基础IL-6分泌下调，转化生长因子-β不诱导任何血管内皮生长因子反应，MMP9减少，MMP2和iNOS表达增加。从TGFBR2(Myeko)小鼠分离的CD11b(+)Gr1(+)细胞在调节Arg、iNOS、VEGF和CXCR4方面没有任何作用，而且这些细胞对T细胞增殖的抑制活性降低。此外，我们还发现，TGFBR2(Myeko)小鼠肿瘤组织中的DC具有更强的抗原提呈特性，并增强了刺激抗原特异性T细胞增殖的能力。我们认为，髓系细胞中的TGFBR2对这些细胞的抗肿瘤功能具有负性调节作用，该受体的缺失降低了CD11b(+)Gr1(+)细胞的抑制功能，增加了DC的抗原提呈特性和TAMs的抗肿瘤特性。J.Leukoc。比奥尔。92：641-651；2012。
By crossing LysM-Cre and TGF-beta type II receptor (Tgfbr2) floxed mice we achieved specific deletion of Tgfbr2 in myeloid cells (Tgfbr2(MyeKO) mice). S.c.-injected (LLC, EL4-OVA) and implanted (MMTV-PyMT) carcinoma cells grow slower in Tgfbr2(MyeKO) mice. The number of CD45(+) cells in the tumor tissue was the same in both genotypes of mice, but upon analysis, the percentage of T cells (CD45(+)CD3(+)) in the KO mice was increased. By flow cytometry analysis, we did not detect any differences in the number and phenotype of TAMs, CD11b(+)Gr1(+), and DCs in Tgfbr2(MyeKO) compared with Tgfbr2(MyeWT) mice. ELISA and qRT-PCR data showed differences in myeloid cell functions. In Tgfbr2(MyeKO) TAMs, TNF-alpha secretion was increased, basal IL-6 secretion was down-regulated, TGF-beta did not induce any VEGF response, and there was decreased MMP9 and increased MMP2 and iNOS expression. TGF-beta did not have any effect on CD11b(+)Gr1(+) cells isolated from Tgfbr2(MyeKO) mice in the regulation of Arg, iNOS, VEGF, and CXCR4, and moreover, these cells have decreased suppressive activity relative to T cell proliferation. Also, we found that DCs from tumor tissue of Tgfbr2(MyeKO) mice have increased antigen-presented properties and an enhanced ability to stimulate antigen-specific T cell proliferation. We conclude that Tgfbr2 in myeloid cells has a negative role in the regulation of anti-tumorigenic functions of these cells, and deletion of this receptor decreases the suppressive function of CD11b(+)Gr1(+) cells and increases antigen-presenting properties of DCs and anti-tumorigenic properties of TAMs. J. Leukoc. Biol. 92: 641-651; 2012.