Targeting MARCO and IL37R on Immunosuppressive Macrophages in Lung Cancer Blocks Regulatory T Cells and Supports Cytotoxic Lymphocyte Function
Targeting MARCO and IL37R on Immunosuppressive Macrophages in Lung Cancer Blocks Regulatory T Cells and Supports Cytotoxic Lymphocyte Function
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DOI：
10.1158/0008-5472.can-20-1885
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发表时间：
2021-02-15
期刊：
影响因子：
11.2
通讯作者：
Sarhan, Dhifaf
中科院分区：
文献类型：
--
作者：
La Fleur, Linnea;Botling, Johan;Sarhan, Dhifaf
实体瘤的进展和转移能力受到肿瘤微环境中免疫细胞的强烈影响。在非小细胞肺癌（NSCLC）中，抗炎性肿瘤相关巨噬细胞（TAM）的蓄积与较差的临床结局和治疗抵抗相关。在此，我们研究了在存在表达具有胶原结构的巨噬细胞受体（MARCO）的肿瘤前TAM的情况下NSCLC的免疫状况。在这些肿瘤中，MARCO表达TAM的数量与调节性T细胞和效应T细胞的出现增加以及自然杀伤（NK）细胞的减少相关。此外，来自肿瘤的转录组学数据揭示了MARCO表达与肿瘤细胞因子IL 37之间的相关性。随后的体外研究表明，肺癌细胞极化巨噬细胞表达MARCO，并通过释放IL 37获得免疫抑制表型。表达MARCO的TAM阻断细胞毒性T细胞和NK细胞活化，抑制它们的增殖、细胞因子产生和肿瘤杀伤能力。机制上，MARCO（+）巨噬细胞增强调节性T（Treg）细胞增殖和IL10产生，并降低CD8 T细胞活性。通过抗体或CRISPR敲除肺癌细胞系中的IL37靶向MARCO或IL37受体（IL37R）使TAM再极化，导致NK细胞和T细胞的恢复的细胞溶解活性和抗肿瘤能力以及下调的Treg细胞活性。总之，我们的数据表明，一种新的免疫治疗方法，靶向人类TAMs免疫抑制NK细胞和T细胞antitumor activities.Significance：这项研究定义肿瘤来源的IL 37和巨噬细胞清道夫受体MARCO作为潜在的治疗靶点，以重塑免疫抑制微环境在肺癌患者。
The progression and metastatic capacity of solid tumors are strongly influenced by immune cells in the tumor microenvironment. In non-small cell lung cancer (NSCLC), accumulation of anti-inflammatory tumor-associated macrophages (TAM) is associated with worse clinical outcome and resistance to therapy. Here we investigated the immune landscape of NSCLC in the presence of protumoral TAMs expressing the macrophage receptor with collagenous structure (MARCO). MARCO-expressing TAM numbers correlated with increased occurrence of regulatory T cells and effector T cells and decreased natural killer (NK) cells in these tumors. Furthermore, transcriptomic data from the tumors uncovered a correlation between MARCO expression and the antiinflammatory cytokine IL37. In vitro studies subsequently showed that lung cancer cells polarized macrophages to express MARCO and gain an immune-suppressive phenotype through the release of IL37. MARCO-expressing TAMs blocked cytotoxic T-cell and NK-cell activation, inhibiting their proliferation, cytokine production, and tumor killing capacity. Mechanistically, MARCO(+) macrophages enhanced regulatory T (Treg) cell proliferation and IL10 production and diminished CD8 T-cell activities. Targeting MARCO or IL37 receptor (IL37R) by antibody or CRISPR knockout of IL37 in lung cancer cell lines repolarized TAMs, resulting in recovered cytolytic activity and antitumoral capacity of NK cells and T cells and down-modulated Treg cell activities. In summary, our data demonstrate a novel immune therapeutic approach targeting human TAMs immune suppression of NK- and T-cell antitumor activities.Significance: This study defines tumor-derived IL37 and the macrophage scavenger receptor MARCO as potential therapeutic targets to remodel the immune-suppressive microenvimnment in patients with lung cancer.