Spatial and phenotypic immune profiling of metastatic colon cancer
Spatial and phenotypic immune profiling of metastatic colon cancer
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DOI：
10.1172/jci.insight.121932
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发表时间：
2018-11-15
期刊：
影响因子：
8
通讯作者：
Frankel, Timothy L.
中科院分区：
文献类型：
--
作者：
Lazarus, Jenny;Maj, Tomasz;Frankel, Timothy L.
对免疫检查点抑制剂的疗效至关重要的是正确选择具有足够肿瘤免疫原性和强大但抑制免疫浸润的患者。在结肠癌中，基于免疫的治疗被批准用于DNA错配修复（MMR）缺陷的患者，在这些患者中，基因突变的积累导致新抗原表达增加，引发被PD-L1/PD-1途径抑制的免疫反应。在这里，我们报告了使用多重荧光免疫组织化学（mfIHC）对mmr缺陷转移性结直肠癌微环境的表征，发现细胞毒性T淋巴细胞（ctl）的浸润增加，ctl更经常与上皮细胞（ECs）结合，并提高了总生存率。一组完整MMR患者的免疫微环境与MMR缺陷患者相似，他们普遍表达高水平的PD-L1，这表明他们可能代表了目前未经治疗的检查点抑制剂应答人群。此外，肿瘤微环境（TME）中抗原呈递细胞（APCs）上PD-L1的表达导致CTL/EC结合受损，Tregs的浸润和结合增强。mfIHC对TME的表征强调了转移性结肠癌中免疫和免疫抑制之间的联系，并可能更好地对接受免疫治疗的患者进行分层。
Paramount to the efficacy of immune checkpoint inhibitors is proper selection of patients with adequate tumor immunogenicity and a robust but suppressed immune infiltrate. In colon cancer, immune-based therapies are approved for patients with DNA mismatch repair (MMR) deficiencies, in whom accumulation of genetic mutations results in increased neoantigen expression, triggering an immune response that is suppressed by the PD-L1/PD-1 pathway. Here, we report that characterization of the microenvironment of MMR-deficient metastatic colorectal cancer using multiplex fluorescent immunohistochemistry (mfIHC) identified increased infiltration of cytotoxic T lymphocytes (CTLs), which were more often engaged with epithelial cells (ECs) and improved overall survival. A subset of patients with intact MMR but a similar immune microenvironment to MMR-deficient patients was identified and found to universally express high levels of PD-L1, suggesting that they may represent a currently untreated, checkpoint inhibitor-responsive population. Further, PD-L1 expression on antigen-presenting cells (APCs) in the tumor microenvironment (TME) resulted in impaired CTL/EC engagement and enhanced infiltration and engagement of Tregs. Characterization of the TME by mfIHC highlights the interconnection between immunity and immunosuppression in metastatic colon cancer and may better stratify patients for receipt of immunotherapies.