Monocytes Differentiate to Immune Suppressive Precursors of Metastasis-Associated Macrophages in Mouse Models of Metastatic Breast Cancer.
Monocytes Differentiate to Immune Suppressive Precursors of Metastasis-Associated Macrophages in Mouse Models of Metastatic Breast Cancer.
复制标题
在转移性乳腺癌的小鼠模型中，单核细胞与转移相关巨噬细胞的免疫抑制前体分化。
DOI：
10.3389/fimmu.2017.02004
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发表时间：
2017
影响因子：
7.3
通讯作者：
Pollard JW
中科院分区：
文献类型：
--
作者：
Kitamura T;Doughty-Shenton D;Cassetta L;Fragkogianni S;Brownlie D;Kato Y;Carragher N;Pollard JW
转移相关巨噬细胞（MAM）通过促进转移癌细胞的外渗和存活，在乳腺癌转移中发挥关键作用。在转移性乳腺癌小鼠模型中，我们之前报道过循环经典单核细胞（C-MO）优先迁移到受肿瘤侵袭的肺部，并在那里分化为 MAM。然而，转移部位 C-MO 的命运和特征尚未确定。在这项研究中，我们发现过继转移的 C-MO (F4/80lowCD11b+Ly6C+) 分化为独特的骨髓细胞群，其特征为 F4/80highCD11bhighLy6Chigh，并在迁移到转移性肺后 18 小时内产生 MAM (F4/80lowCD11bhighLy6Clow)。在乳腺癌小鼠模型中，CD11bhighLy6Chigh MAM 前体细胞 (MAMPC) 常见于转移性肺中，并且它们的积累在转移性肿瘤生长过程中增加。 MAMPC 的形态和基因表达谱与 C-MO 不同，与 MAM 具有更大的相似性。例如，MAMPC 表达成熟巨噬细胞标志物，如 CD14、CD36、CD64 和 CD206，其水平与 MAM 相当，表明 MAMPC 已在肿瘤微环境中形成巨噬细胞谱系。 MAMPC 还表达比 C-MO 更高水平的 Arg1、Hmox1 和 Stab1，达到与 MAM 相当的水平。通过基因删除集落刺激因子 1 受体 (CSF1R)，这些 MAM 相关基因在 MAMPC 中的表达降低。另一方面，短暂的 CSF1R 阻断并没有减少转移部位 MAMPC 的数量，这表明 CSF1 信号传导在 MAMPC 中活跃，但不是它们积累所必需的。在功能上，MAMPC 部分通过超氧化物的产生来抑制体外激活的 CD8+ T 细胞的细胞毒性。总体而言，我们的结果表明，在迁移到转移性肿瘤后，C-MO 立即分化为具有单核骨髓源性抑制细胞表型特征的免疫抑制细胞，并且可能有针对性地增强转移性乳腺癌免疫治疗的疗效。
Metastasis-associated macrophages (MAMs) play pivotal roles in breast cancer metastasis by promoting extravasation and survival of metastasizing cancer cells. In a metastatic breast cancer mouse model, we previously reported that circulating classical monocytes (C-MOs) preferentially migrated into the tumor-challenged lung where they differentiated into MAMs. However, the fate and characteristics of C-MOs in the metastatic site has not been defined. In this study, we identified that adoptively transferred C-MOs (F4/80lowCD11b+Ly6C+) differentiated into a distinct myeloid cell population that is characterized as F4/80highCD11bhighLy6Chigh and gives rise to MAMs (F4/80lowCD11bhighLy6Clow) within 18 h after migration into the metastatic lung. In mouse models of breast cancer, the CD11bhighLy6Chigh MAM precursor cells (MAMPCs) were commonly found in the metastatic lung, and their accumulation was increased during metastatic tumor growth. The morphology and gene expression profile of MAMPCs were distinct from C-MOs and had greater similarity to MAMs. For example MAMPCs expressed mature macrophage markers such as CD14, CD36, CD64, and CD206 at comparable levels with MAMs, suggesting that MAMPCs have committed to a macrophage lineage in the tumor microenvironment. MAMPCs also expressed higher levels of Arg1, Hmox1, and Stab1 than C-MOs to a comparable level to MAMs. Expression of these MAM-associated genes in MAMPCs was reduced by genetic deletion of colony-stimulating factor 1 receptor (CSF1R). On the other hand, transient CSF1R blockade did not reduce the number of MAMPCs in the metastatic site, suggesting that CSF1 signaling is active in MAMPCs but is not required for their accumulation. Functionally MAMPCs suppressed the cytotoxicity of activated CD8+ T cells in vitro in part through superoxide production. Overall, our results indicate that immediately following migration into the metastatic tumors C-MOs differentiate into immunosuppressive cells that have characteristics of monocytic myeloid-derived suppressor cell phenotype and might be targeted to enhance efficacy of immunotherapy for metastatic breast cancer.