Thomas Claire E, Takashima Yasutoshi, Buchanan Daniel D, Wesselink Evertine, Qu Conghui, Hsu Li, Dias Costa Andressa, Gallinger Steven, Grant Robert C, Huyghe Jeroen R, Thomas Sushma, Ugai Satoko, Zhong Yuxue, Matsuda Kosuke, Ugai Tomotaka, Peters Ulrike, Ogino Shuji, Nowak Jonathan A, Phipps Amanda I
Fred Hutchinson Cancer Center, Seattle, WA, United States.
Brigham and Women's Hospital, Boston, MA, United States.
Cancer Epidemiol Biomarkers Prev. 2025 Apr 17. doi: 10.1158/1055-9965.EPI-25-0287.
Prior studies have demonstrated that the overall density of T cells in colorectal tumors is favorably associated with colorectal cancer (CRC) survival; however, few studies have considered the potentially distinct roles of heterogeneous T cell subsets in different tissue regions in relation to CRC outcomes.
Including 1,113 CRC tumors from three observational studies, we conducted in-situ T cell profiling using a customized 9-plex [CD3, CD4, CD8, CD45RA, CD45RO, FOXP3, KRT (keratin), MKI67 (Ki-67), and DAPI] multispectral immunofluorescence assay. Multivariable-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of T cell subset densities in both epithelial and stromal tissue areas in CRC with disease-specific survival.
Higher CD3+CD4+ and CD3+CD8+ naive, memory, and regulatory T cell densities were significantly associated with better CRC-specific survival in both epithelial and stromal tissue areas (HRs highest quantile versus lowest quantile ranging 0.41-0.68). These associations persisted in models further adjusted for stage at diagnosis and were largely consistent when stratified by microsatellite instability (MSI) status. However, the further stratification into CD4+ or CD8+ T cell subsets beyond CD3+ subsets did not significantly improve how well our model explains CRC prognosis.
The density of T cells in CRC tissue, both overall and for several T cell subset populations, is significantly associated with CRC-specific survival independent of MSI status and stage at diagnosis.
Higher levels of T cell densities in different locations with different functions are associated with better CRC-specific survival.
先前的研究表明，结直肠癌肿瘤中T细胞的总体密度与结直肠癌（CRC）的生存率呈正相关；然而，很少有研究考虑不同组织区域中异质性T细胞亚群在CRC预后方面可能具有的不同作用。
我们纳入了三项观察性研究中的1113例CRC肿瘤，使用定制的9重[CD3、CD4、CD8、CD45RA、CD45RO、FOXP3、角蛋白（KRT）、MKI67（Ki-67）和DAPI]多光谱免疫荧光检测法进行原位T细胞分析。采用多变量调整的Cox比例风险模型来估计CRC上皮和基质组织区域中T细胞亚群密度与疾病特异性生存之间关联的风险比（HR）和95%置信区间（CI）。
上皮和基质组织区域中较高的CD3⁺CD4⁺和CD3⁺CD8⁺初始、记忆和调节性T细胞密度均与更好的CRC特异性生存显著相关（HR最高四分位数与最低四分位数范围为0.41 - 0.68）。这些关联在进一步调整诊断分期的模型中仍然存在，并且在按微卫星不稳定性（MSI）状态分层时基本一致。然而，在CD3⁺亚群之外进一步细分为CD4⁺或CD8⁺T细胞亚群并没有显著改善我们的模型对CRC预后的解释能力。
CRC组织中T细胞的密度，无论是总体密度还是几个T细胞亚群的密度，均与CRC特异性生存显著相关，且独立于MSI状态和诊断分期。
不同位置具有不同功能的较高T细胞密度水平与更好的CRC特异性生存相关。
