Control of tumor-associated macrophage alternative activation by macrophage migration inhibitory factor.
Control of tumor-associated macrophage alternative activation by macrophage migration inhibitory factor.
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DOI：
10.4049/jimmunol.1201650
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发表时间：
2013-03-15
期刊：
影响因子：
--
通讯作者：
Mitchell RA
中科院分区：
文献类型：
--
作者：
Yaddanapudi K;Putty K;Rendon BE;Lamont GJ;Faughn JD;Satoskar A;Lasnik A;Eaton JW;Mitchell RA
肿瘤基质替代性激活的巨噬细胞是抗肿瘤 T 淋巴细胞反应、瘤内新血管形成和转移扩散的重要决定因素。我们最近研究巨噬细胞迁移抑制因子（MIF）拮抗抗黑色素瘤免疫反应的机制，结果表明巨噬细胞来源的MIF参与黑色素瘤小鼠巨噬细胞的选择性激活。与来自携带肿瘤的 MIF 野生型小鼠的巨噬细胞相比，从携带 MIF 缺陷的黑色素瘤小鼠中分离的外周巨噬细胞和肿瘤相关巨噬细胞 (TAM) 均表现出促炎细胞因子表达升高，并减少抗炎、免疫抑制和促血管生成基因产物。此外，与野生型同窝小鼠相比，MIF 缺陷小鼠的 TAM 和骨髓源性抑制细胞 (MDSC) 表现出 T 淋巴细胞免疫抑制活性降低。与 TAM 降低的肿瘤免疫抑制和新血管生成潜力相对应，MIF 缺陷可防止可移植的皮下黑色素瘤生长和黑色素瘤肺转移定植。最后，我们首次报道了我们之前发现的 MIF 小分子拮抗剂 4-碘-6-苯基嘧啶 (4-IPP)，在体外和体内重现了 MIF 缺陷，并减弱了肿瘤极化巨噬细胞替代激活、免疫抑制、新血管生成和黑色素瘤生长。这些研究描述了 MIF 对肿瘤相关巨噬细胞选择性激活的重要功能贡献，并为黑色素瘤患者中 MIF 的免疫治疗靶向提供了依据。
Tumor stromal alternatively activated macrophages are important determinants of anti-tumor T lymphocyte responses, intratumoral neovascularization and metastatic dissemination. Our recent efforts to investigate the mechanism of macrophage migration inhibitory factor (MIF) in antagonizing anti-melanoma immune responses reveal that macrophage-derived MIF participates in macrophage alternative activation in melanoma-bearing mice. Both peripheral and tumor-associated macrophages (TAMs) isolated from melanoma bearing MIF-deficient mice display elevated pro-inflammatory cytokine expression and reduced anti-inflammatory, immunosuppressive and pro-angiogenic gene products compared to macrophages from tumor bearing MIF wildtype mice. Moreover, TAMs and myeloid-derived suppressor cells (MDSCs) from MIF-deficient mice exhibit reduced T lymphocyte immunosuppressive activities than do those from their wildtype littermates. Corresponding with reduced tumor immunosuppression and neoangiogenic potential by TAMs, MIF-deficiency confers protection against transplantable subcutaneous melanoma outgrowth and melanoma lung metastatic colonization. Finally, we report for the first time that our previously discovered MIF small molecule antagonist, 4-iodo-6-phenylpyrimidine (4-IPP), recapitulates MIF-deficiency in vitro and in vivo and attenuates tumor polarized macrophage alternative activation, immunosuppression, neoangiogenesis and melanoma tumor outgrowth. These studies describe an important functional contribution by MIF to tumor-associated macrophage alternative activation and provide justification for immunotherapeutic targeting of MIF in melanoma patients.
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影响因子：
4.4
作者：
Abe, R;Peng, T;Metz, CN
通讯作者：
Metz, CN
影响因子：
82.9
作者：
Donnelly, SC;Haslett, C;Bucala, R
通讯作者：
Bucala, R
影响因子：
20.3
作者：
Biswas, SK;Gangi, L;Sica, A
通讯作者：
Sica, A
DOI：
10.1073/pnas.95.19.11383
发表时间：
1998-09-15
影响因子：
11.1
作者：
Calandra, T;Spiegel, LA;Bucala, R
通讯作者：
Bucala, R
影响因子：
2.5
作者：
Liao, Bing;Zhong, Bi-Ling;Li, Bin
通讯作者：
Li, Bin