肿瘤细胞在非小细胞肺癌肿瘤微环境的新型体外共培养模型中调节巨噬细胞表型。
Tumor Cells Modulate Macrophage Phenotype in a Novel In Vitro Co-Culture Model of the NSCLC Tumor Microenvironment.
机构信息
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas; Cancer Biology Graduate Program, University of Texas Southwestern Medical Center, Dallas, Texas.
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas; Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas.
出版信息
J Thorac Oncol. 2022 Oct;17(10):1178-1191. doi: 10.1016/j.jtho.2022.06.011. Epub 2022 Jul 5.
INTRODUCTION
Macrophage phenotype in the tumor microenvironment correlates with prognosis in NSCLC. Immunosuppressive macrophages promote tumor progression, whereas proinflammatory macrophages may drive an antitumor immune response. How individual NSCLCs affect macrophage phenotype is a major knowledge gap.
METHODS
To systematically study the impact of lung cancer cells on macrophage phenotypes, we developed an in vitro co-culture model that consisted of molecularly and clinically annotated patient-derived NSCLC lines, human cancer-associated fibroblasts, and murine macrophages. Induced macrophage phenotype was studied through quantitative real-time polymerase chain reaction and validated in vivo using NSCLC xenografts through quantitative immunohistochemistry and clinically with The Cancer Genome Atlas (TCGA)-"matched" patient tumors.
RESULTS
A total of 72 NSCLC cell lines were studied. The most frequent highly induced macrophage-related gene was Arginase-1, reflecting an immunosuppressive M2-like phenotype. This was independent of multiple clinicopathologic factors, which also did not affect M2:M1 ratios in matched TCGA samples. In vivo, xenograft tumors established from high Arginase-1-inducing lines (Arg) had a significantly elevated density of Arg1+ macrophages. Matched TCGA clinical samples to Arg NSCLC lines had a significantly higher ratio of M2:M1 macrophages (p = 0.0361).
CONCLUSIONS
In our in vitro co-culture model, a large panel of patient-derived NSCLC lines most frequently induced high-expression Arginase-1 in co-cultured mouse macrophages, independent of major clinicopathologic and oncogenotype-related factors. Arg cluster-matched TCGA tumors contained a higher ratio of M2:M1 macrophages. Thus, this in vitro model reproducibly characterizes how individual NSCLC modulates macrophage phenotype, correlates with macrophage polarization in clinical samples, and can serve as an accessible platform for further investigation of macrophage-specific therapeutic strategies.
简介
肿瘤微环境中的巨噬细胞表型与 NSCLC 的预后相关。免疫抑制性巨噬细胞促进肿瘤进展，而促炎巨噬细胞可能引发抗肿瘤免疫反应。单个 NSCLC 如何影响巨噬细胞表型是一个主要的知识空白。
方法
为了系统地研究肺癌细胞对巨噬细胞表型的影响，我们开发了一种体外共培养模型，该模型由分子和临床注释的患者来源 NSCLC 系、人癌症相关成纤维细胞和鼠巨噬细胞组成。通过定量实时聚合酶链反应研究诱导的巨噬细胞表型，并通过 NSCLC 异种移植在体内进行验证，通过 TCGA-“匹配”患者肿瘤进行临床验证。
结果
共研究了 72 种 NSCLC 细胞系。最常见的高度诱导巨噬细胞相关基因是精氨酸酶-1，反映出一种免疫抑制的 M2 样表型。这与多种临床病理因素无关，也不影响匹配 TCGA 样本中的 M2:M1 比值。在体内，从高精氨酸酶-1诱导系（Arg）建立的异种移植肿瘤中 Arg1+巨噬细胞的密度显著升高。与 Arg NSCLC 系匹配的 TCGA 临床样本中 M2:M1 巨噬细胞的比例显著更高（p = 0.0361）。
结论
在我们的体外共培养模型中，一组大型患者来源的 NSCLC 系最常诱导共培养的鼠巨噬细胞中高表达精氨酸酶-1，这与主要的临床病理和致癌基因型相关因素无关。Arg 聚类匹配的 TCGA 肿瘤中 M2:M1 巨噬细胞的比例更高。因此，这种体外模型可重现地描述单个 NSCLC 如何调节巨噬细胞表型，与临床样本中的巨噬细胞极化相关，并可作为进一步研究巨噬细胞特异性治疗策略的便捷平台。
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