Coordination of Intratumoral Immune Reaction and Human Colorectal Cancer Recurrence
Coordination of Intratumoral Immune Reaction and Human Colorectal Cancer Recurrence
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DOI：
10.1158/0008-5472.can-08-2654
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发表时间：
2009-03-15
期刊：
影响因子：
11.2
通讯作者：
Galon, Jerome
中科院分区：
文献类型：
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作者：
Camus, Matthieu;Tosolini, Marie;Galon, Jerome
免疫系统在控制实体瘤进展中的作用已在几种小鼠模型中确立。然而，在人类癌症的背景下，免疫应答和肿瘤逃逸对患者预后的影响知之甚少。在这里，我们调查的细胞和分子参数，可以描述在人结直肠癌的原位免疫反应，根据转移性淋巴结或远处器官浸润（Meta-或Meta+患者）的临床参数。通过整合与免疫和促肿瘤过程相关的大规模表型（流式细胞术，39例患者）和基因表达（真实的时间逆转录-PCR，103例患者）数据集，分析结直肠癌的原发肿瘤样品。在具有高密度T细胞的Meta-结直肠癌原发性肿瘤中，我们观察到先天免疫细胞标志物[肿瘤相关巨噬细胞、树突状细胞、自然杀伤（NK）细胞和NKT细胞]与早期活化T细胞标志物之间存在显著正相关。细胞毒性和效应记忆T细胞亚群的标志物之间也观察到显着的相关性。这些相关性在低T细胞浸润的肿瘤中不存在，在高T细胞浸润的Meta+肿瘤中改变。我们发现，介导细胞毒性（GNLY）和Th 1适应性免疫反应（IRF 1）的基因的共表达准确预测患者的生存独立的转移状态。肿瘤内促血管生成介质血管内皮生长因子的高mRNA表达与GNLY高mRNA表达患者的生存率显著降低相关。对结直肠癌原发性肿瘤微环境的研究使我们能够揭示有利结果与肿瘤内免疫应答的有效协调之间的关联。[Cancer Res 2009;69（6）：2685-93]
A role for the immune system in controlling the progression of solid tumors has been established in several mouse models. However, the effect of immune responses and tumor escape on patient prognosis in the context of human cancer is poorly understood. Here, we investigate the cellular and molecular parameters that could describe in situ immune responses in human colorectal cancer according to clinical parameters of metastatic lymph node or distant organ invasion (META- or META+ patients). Primary tumor samples of colorectal carcinoma were analyzed by integrating large-scale phenotypic (flow cytometry, 39 patients) and gene expression (real time reverse transcription-PCR, 103 patients) data sets related to immune and protumoral processes. In META- colorectal cancer primary tumors with high densities of T cells, we observed significant positive correlations between markers of innate immune cells [tumor-associated macrophages, dendritic cells, natural killer (NK) cells, and NKT cells] and markers of early-activated T cells. Significant correlations were also observed between markers of cytotoxic and effector memory T-cell subpopulations. These correlation profiles were absent in tumors with low T-cell infiltrates and were altered in META+ tumors with high T-cell infiltrates. We show that the coexpression of genes mediating cytotoxicity (GNLY) and Th1 adaptive immune responses (IRF1) accurately predicted patient survival independently of the metastatic status. High intratumoral mRNA expression of the proangiogenic mediator vascular endothelial growth factor was associated with significantly reduced survival rates in patients expressing high mRNA levels of GNLY. Investigation of the colorectal cancer primary tumor microenvironment allowed us to uncover the association of favorable outcomes with efficient coordination of the intratumoral immune response. [Cancer Res 2009;69(6):2685-93]