The Vigorous Immune Microenvironment of Microsatellite Instable Colon Cancer Is Balanced by Multiple Counter-Inhibitory Checkpoints
The Vigorous Immune Microenvironment of Microsatellite Instable Colon Cancer Is Balanced by Multiple Counter-Inhibitory Checkpoints
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DOI：
10.1158/2159-8290.cd-14-0863
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发表时间：
2015-01-01
期刊：
影响因子：
28.2
通讯作者：
Housseau, Franck
中科院分区：
文献类型：
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作者：
Llosa, Nicolas J.;Cruise, Michael;Housseau, Franck
我们用免疫组织化学、激光捕获显微切割/qRT-PCR、流式细胞术和肿瘤浸润性淋巴细胞的功能分析检测了原发性结直肠癌的免疫微环境。部分结直肠癌组织中CD8(+)细胞毒性T淋巴细胞(CTL)活化，Th1细胞活化，以产生干扰素-γ和Th1转录因子Tbet为特征。对肿瘤基因类型的平行分析显示，几乎所有具有这种活跃的Th1/CTL微环境的肿瘤都存在错配修复缺陷，这一点以微卫星不稳定性(MSI)为证据。抵消了这种活跃的Th1/CTL微环境，MSI肿瘤选择性地表现出多个免疫检查点的高度上调表达，包括5个免疫检查点-PD-1、PD-L1、CTLA-4、LAG-3和IDO-目前正作为抑制剂的临床靶点。这些发现将肿瘤基因型与免疫微环境联系起来，并解释了为什么MSI肿瘤不能自然消除，尽管有敌对的Th1/CTL微环境。他们进一步表明，阻断特定的检查点可能在结直肠癌的MSI亚型中选择性有效。意义：本文报道的发现首次证明了肿瘤微环境中遗传定义的癌症亚型与其相应的免疫检查点表达之间的联系。错配修复缺陷的结直肠癌亚群选择性地上调至少五个检查点分子，这些分子是目前正在进行临床测试的抑制剂的靶标。(C)2014年AACR。
We examined the immune microenvironment of primary colorectal cancer using immunohistochemistry, laser capture microdissection/qRT-PCR, flow cytometry, and functional analysis of tumor-infiltrating lymphocytes. A subset of colorectal cancer displayed high infiltration with activated CD8(+) cytotoxic T lymphocyte (CTL) as well as activated Th1 cells characterized by IFN gamma production and the Th1 transcription factor TBET. Parallel analysis of tumor genotypes revealed that virtually all of the tumors with this active Th1/CTL microenvironment had defects in mismatch repair, as evidenced by microsatellite instability (MSI). Counterbalancing this active Th1/CTL microenvironment, MSI tumors selectively demonstrated highly upregulated expression of multiple immune checkpoints, including five-PD-1, PD-L1, CTLA-4, LAG-3, and IDO-currently being targeted clinically with inhibitors. These findings link tumor genotype with the immune microenvironment, and explain why MSI tumors are not naturally eliminated despite a hostile Th1/CTL microenvironment. They further suggest that blockade of specific checkpoints may be selectively efficacious in the MSI subset of colorectal cancer.SIGNIFICANCE: The findings reported in this article are the first to demonstrate a link between a genetically defined subtype of cancer and its corresponding expression of immune checkpoints in the tumor microenvironment. The mismatch repair-defective subset of colorectal cancer selectively upregulates at least five checkpoint molecules that are targets of inhibitors currently being clinically tested. (C)2014 AACR.