Chemerin Suppresses Breast Cancer Growth by Recruiting Immune Effector Cells Into the Tumor Microenvironment
Chemerin Suppresses Breast Cancer Growth by Recruiting Immune Effector Cells Into the Tumor Microenvironment
复制标题
Chemerin通过募集免疫效应细胞进入肿瘤微环境抑制乳腺癌生长
DOI：
10.3389/fimmu.2019.00983
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发表时间：
2019-05-08
影响因子：
7.3
通讯作者：
Zabel, Brian A.
中科院分区：
文献类型：
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作者：
Pachynski, Russell K.;Wang, Ping;Zabel, Brian A.
免疫细胞浸润到肿瘤微环境（TME）中可以调节肿瘤细胞的生长和存活，影响肿瘤发生和肿瘤进展。肿瘤中存在的效应免疫细胞数量与许多人类肿瘤（包括乳腺癌）的临床结局之间的相关性已得到广泛描述。目前利用检查点抑制剂或共刺激分子激动剂的免疫疗法旨在激活效应免疫细胞。然而，肿瘤通常在TME内缺乏足够的效应细胞数量，导致对这些药剂的次优应答。趋化蛋白（RARRES 2）是一种广泛表达于许多组织中的白细胞化学引诱物，已知可募集先天性白细胞。CMKLR 1是趋化因子的趋化细胞受体，在树突细胞、NK细胞和巨噬细胞亚群上表达。我们以前已经表明，chemerin作为一种肿瘤抑制细胞因子在小鼠黑色素瘤模型中招募先天性免疫防御到TME。与正常组织对应物相比，Chemerin/RARRES 2在许多肿瘤中下调，包括乳腺癌。在这里，使用同基因原位EMT 6乳腺癌模型，我们表明，被迫过度表达chemerin的肿瘤细胞的结果在TME内的NK细胞和T细胞的显着招聘。虽然EMT 6细胞分泌chemerin并没有改变其体外表型行为，但它确实显著抑制了体内肿瘤生长。为了确定这种抗肿瘤表型所需的细胞效应物，我们耗尽了NK细胞或CD 8（+）T细胞，发现两种细胞类型都是EMT 6肿瘤生长的趋化因子依赖性抑制所需的。最后，我们发现与匹配的正常组织相比，人类乳腺癌样本中RARRES 2 mRNA的水平显著降低。因此，我们第一次表明，增加乳腺癌TME内chemerin的表达可以通过募集NK和T细胞来抑制生长，从而支持这种方法作为一种有前途的免疫策略。
Infiltration of immune cells into the tumor microenvironment (TME) can regulate growth and survival of neoplastic cells, impacting tumorigenesis and tumor progression. Correlations between the number of effector immune cells present in a tumor and clinical outcomes in many human tumors, including breast, have been widely described. Current immunotherapies utilizing checkpoint inhibitors or co-stimulatory molecule agonists aim to activate effector immune cells. However, tumors often lack adequate effector cell numbers within the TME, resulting in suboptimal responses to these agents. Chemerin (RARRES2) is a leukocyte chemoattractant widely expressed in many tissues and is known to recruit innate leukocytes. CMKLR1 is a chemotactic cellular receptor for chemerin and is expressed on subsets of dendritic cells, NK cells, and macrophages. We have previously shown that chemerin acts as a tumor suppressive cytokine in mouse melanoma models by recruiting innate immune defenses into the TME. Chemerin/RARRES2 is down-regulated in many tumors, including breast, compared to normal tissue counterparts. Here, using a syngeneic orthotopic EMT6 breast carcinoma model, we show that forced overexpression of chemerin by tumor cells results in significant recruitment of NK cells and T cells within the TME. While chemerin secretion by EMT6 cells did not alter their phenotypic behavior in vitro, it did significantly suppress tumor growth in vivo. To define the cellular effectors required for this anti-tumor phenotype, we depleted NK cells or CD8(+) T cells and found that either cell type is required for chemerin-dependent suppression of EMT6 tumor growth. Finally, we show significantly reduced levels of RARRES2 mRNA in human breast cancer samples compared to matched normal tissues. Thus, for the first time we have shown that increasing chemerin expression within the breast carcinoma TME can suppress growth by recruitment of NK and T cells, thereby supporting this approach as a promising immunotherapeutic strategy.