Active immunosurveillance in the tumor microenvironment of colorectal cancer is associated with low frequency tumor budding and improved outcome
Active immunosurveillance in the tumor microenvironment of colorectal cancer is associated with low frequency tumor budding and improved outcome
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DOI：
10.1016/j.trsl.2015.02.008
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发表时间：
2015-08-01
影响因子：
7.8
通讯作者：
Zlobec, Inti
中科院分区：
文献类型：
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作者：
Koelzer, Viktor H.;Dawson, Heather;Zlobec, Inti
结直肠癌（CRC）侵袭前的肿瘤出芽（单个肿瘤细胞或小肿瘤细胞簇）是与上皮-间质转化相关的不良预后指标。本研究通过分析I类主要组织相容性复合体（MHC）在侵袭性肿瘤细胞室中的表达来表征肿瘤芽的免疫原性。我们假设维持功能性MHC-I抗原呈递途径，激活CD8+ 1细胞，释放肿瘤微环境中的抗肿瘤效应分子，如细胞毒性颗粒相关RNA结合蛋白（TIA1），可以对抗肿瘤出芽并有利于延长患者的预后。因此，通过免疫组织化学对220个crc进行了表征良好的多孔组织芯片mhc - 1、CD8和TIA1的分析。使用全组织切片（n = 100）进行MHC-I的地形表达分析。研究了Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）和B-Raf原癌基因、丝氨酸/苏氨酸激酶（BRAF）突变、错配修复（MMR）蛋白表达和cpg岛甲基化表型（CIMP）。我们的研究结果表明，细胞膜上的MHC-I表达在侵袭过程中经常下调。侵袭前沿维持MHC-I强烈预测低级别肿瘤出芽（P = 0.0004）。肿瘤微环境中MHC-I/CD8/TIA1三阳性预测早期t期（P = 0.0031），无淋巴结转移（P = 0.0348），淋巴（P = 0.0119）和静脉侵袭（P = 0.006），以及非常有利的5年生存率（三阴性患者90.9% vs 39.3%, P = 0.0032）。MHC-I丢失在kras突变的CD8+ CRC中很常见（P = 0.0228）。与CIMP、MMR或BRAF突变没有关系。综上所述，肿瘤芽可能通过下调细胞膜MHC-I来逃避免疫识别。MHC-I/CD8/TIA1的联合谱提高了抗肿瘤效应细胞的预后价值，应该优先于单一标记方法。
Tumor budding (single tumor cells or small tumor cell clusters) at the invasion front of colorectal cancer (CRC) is an adverse prognostic indicator linked to epithelial-mesenchymal transition. This study characterized the immunogenicity of tumor buds by analyzing the expression of the major histocompatibility complex (MHC) class I in the invasive tumor cell compartment. We hypothesized that maintenance of a functional MHC-I antigen presentation pathway, activation of CD8+ 1-cells, and release of antitumoral effector molecules such as cytotoxic granule-associated RNA binding protein (TIA1) in the tumor microenvironment can counter tumor budding and favor prolonged patient outcome. Therefore, a well-characterized multipunch tissue microarray of 220 CRCs was profiled for MHC-I, CD8, and TIA1 by immunohistochemistry. Topographic expression analysis of MHC-I was performed using whole tissue sections (n = 100). Kirsten rat sarcoma viral oncogene homolog (KRAS) and B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations, mismatch repair (MMR) protein expression, and CpG-island methylator phenotype (CIMP) were investigated. Our results demonstrated that membranous MHC-I expression is frequently down-regulated in the process of invasion. Maintained MHC-I at the invasion front strongly predicted low-grade tumor budding (P = 0.0004). Triple-positive MHC-I/CD8/TIA1 in the tumor microenvironment predicted early T-stage (P = 0.0031), absence of lymph node metastasis (P = 0.0348), lymphatic (P = 0.0119) and venous invasion (P = 0.006), and highly favorable 5-year survival (90.9% vs 39.3% in triple-negative patients; P = 0.0032). MHC-I loss was frequent in KRAS-mutated, CD8+ CRC (P = 0.0228). No relationship was observed with CIMP, MMR, or BRAF mutation. In conclusion, tumor buds may evade immune recognition through downregulation of membranous MHC-I. A combined profile of MHC-I/CD8/TIA1 improves the prognostic value of antitumoral effector cells and should be preferred to a single marker approach.