MicroRNA MIR21 and T Cells in Colorectal Cancer.
MicroRNA MIR21 and T Cells in Colorectal Cancer.
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MicroRNA MIR21与结直肠癌中的T细胞
DOI：
10.1158/2326-6066.cir-15-0084
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发表时间：
2016-01
影响因子：
10.1
通讯作者：
Ogino S
中科院分区：
文献类型：
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作者：
Mima K;Nishihara R;Nowak JA;Kim SA;Song M;Inamura K;Sukawa Y;Masuda A;Yang J;Dou R;Nosho K;Baba H;Giovannucci EL;Bowden M;Loda M;Giannakis M;Bass AJ;Dranoff G;Freeman GJ;Chan AT;Fuchs CS;Qian ZR;Ogino S
结直肠肿瘤和肿瘤微环境中免疫细胞之间复杂的相互作用仍有待阐明。实验证据表明microRNA MIR 21（miR-21）抑制抗肿瘤T细胞介导的免疫。因此，我们假设肿瘤MIR 21表达可能与结直肠癌组织中的T细胞密度呈负相关。利用护士健康研究和卫生专业人员随访研究中的538例直肠癌和结肠癌病例，我们通过定量逆转录聚合酶链反应测定肿瘤MIR 21的表达。采用组织芯片免疫组化和计算机图像分析技术检测肿瘤组织中CD 3+、CD 8+、CD 45 RO（PTPRC）+和FOXP 3+细胞密度。进行有序逻辑回归分析，以评估MIR 21表达（有序四分位数作为预测变量）与T细胞密度（有序四分位数作为结果变量）的相关性，调整肿瘤分子特征，包括微卫星不稳定性; CpG岛甲基化表型; KRAS、BRAF和PIK 3CA突变;以及LINE-1甲基化。我们将双侧α水平调整为0.012进行多重假设检验。肿瘤细胞MIR 21表达与CD 3+和CD 45 RO+细胞密度呈负相关（P趋势< 0.0005）。对于CD 3+或CD 45 RO+细胞四分位数类别单位增加，MIR 21最高与最低四分位数的多变量比值比分别为0.44（95%置信区间[CI]，0.28至0.68）或0.41（95% CI，0.26至0.64）。我们的数据支持肿瘤表观遗传失调的非编码RNA在抑制抗肿瘤T细胞介导的适应性免疫应答中的可能作用，并建议MIR 21作为结直肠癌免疫治疗和预防的潜在靶点。
The complex interactions between colorectal neoplasia and immune cells in the tumor microenvironment remain to be elucidated. Experimental evidence suggests that microRNA MIR21 (miR-21) suppresses antitumor T-cell–mediated immunity. Thus, we hypothesized that tumor MIR21 expression might be inversely associated with T-cell density in colorectal carcinoma tissue. Utilizing 538 rectal and colon cancer cases in the Nurses’ Health Study and the Health Professionals Follow-up Study, we measured tumor MIR21 expression by quantitative reverse-transcription polymerase chain reaction assay. Densities of CD3+, CD8+, CD45RO (PTPRC)+ and FOXP3+ cells in tumor tissue were determined by tissue microarray immunohistochemistry and computer-assisted image analysis. Ordinal logistic regression analysis was conducted to assess the association of MIR21 expression (ordinal quartiles as a predictor variable) with T-cell density (ordinal quartiles as an outcome variable), adjusting for tumor molecular features including microsatellite instability; CpG island methylator phenotype; KRAS, BRAF, and PIK3CA mutations; and LINE-1 methylation. We adjusted two-sided α level to 0.012 for multiple hypothesis testing. Tumor MIR21 expression was inversely associated with densities of CD3+ and CD45RO+ cells (Ptrend < 0.0005). Multivariate odds ratio of the highest vs. lowest quartile of MIR21 for a unit increase in quartile categories of CD3+ or CD45RO+ cells was 0.44 (95% confidence interval [CI], 0.28 to 0.68) or 0.41 (95% CI, 0.26 to 0.64), respectively. Our data support a possible role of tumor epigenetic deregulation by non-coding RNA in suppressing antitumor T-cell–mediated adaptive immune response, and suggest MIR21 as a potential target for immunotherapy and prevention in colorectal cancer.