Kamal Yasmin, Dwan Dennis, Hoehn Hannah J, Sanz-Pamplona Rebeca, Alonso M Henar, Moreno Victor, Cheng Chao, Schell Michael J, Kim Youngchul, Felder Seth I, Rennert Hedy S, Melas Marilena, Lazaris Charalampos, Bonner Joseph D, Siegel Erin M, Shibata David, Rennert Gad, Gruber Stephen B, Frost H Robert, Amos Christopher I, Schmit Stephanie L
Department of Biomedical Data Sciences, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Oncoimmunology. 2021 Mar 9;10(1):1862529. doi: 10.1080/2162402X.2020.1862529.
A substantial fraction of patients with stage I-III colorectal adenocarcinoma (CRC) experience disease relapse after surgery with curative intent. However, biomarkers for predicting the likelihood of CRC relapse have not been fully explored. Therefore, we assessed the association between tumor infiltration by a broad array of innate and adaptive immune cell types and CRC relapse risk. We implemented a discovery-validation design including a discovery dataset from Moffitt Cancer Center (MCC; Tampa, FL) and three independent validation datasets: (1) GSE41258 (2) the Molecular Epidemiology of Colorectal Cancer (MECC) study, and (3) GSE39582. Infiltration by 22 immune cell types was inferred from tumor gene expression data, and the association between immune infiltration by each cell type and relapse-free survival was assessed using Cox proportional hazards regression. Within each of the four independent cohorts, CD4+ memory activated T cell (HR: 0.93, 95% CI: 0.90-0.96; FDR = 0.0001) infiltration was associated with longer time to disease relapse, independent of stage, microsatellite instability, and adjuvant therapy. Based on our meta-analysis across the four datasets, 10 innate and adaptive immune cell types associated with disease relapse of which 2 were internally validated using multiplex immunofluorescence. Moreover, immune cell type infiltration was a better predictors of disease relapse than Consensus Molecular Subtype (CMS) and other expression-based biomarkers (Immune-AIC:238.1-238.9; CMS-AIC: 241.0). These data suggest that transcriptome-derived immune profiles are prognostic indicators of CRC relapse and quantification of both innate and adaptive immune cell types may serve as candidate biomarkers for predicting prognosis and guiding frequency and modality of disease surveillance.
相当一部分I-III期结直肠癌（CRC）患者在接受根治性手术后会出现疾病复发。然而，用于预测CRC复发可能性的生物标志物尚未得到充分探索。因此，我们评估了多种先天性和适应性免疫细胞类型的肿瘤浸润与CRC复发风险之间的关联。我们采用了发现-验证设计，包括来自莫菲特癌症中心（MCC；佛罗里达州坦帕）的发现数据集和三个独立的验证数据集：（1）GSE41258，（2）结直肠癌分子流行病学（MECC）研究，以及（3）GSE39582。从肿瘤基因表达数据推断出22种免疫细胞类型的浸润情况，并使用Cox比例风险回归评估每种细胞类型的免疫浸润与无复发生存之间的关联。在四个独立队列中的每一个队列中，CD4+记忆性活化T细胞（HR：0.93，95%CI：0.90-0.96；FDR = 0.0001）浸润与疾病复发时间延长相关，独立于分期、微卫星不稳定性和辅助治疗。基于我们对四个数据集的荟萃分析，有10种先天性和适应性免疫细胞类型与疾病复发相关，其中2种通过多重免疫荧光进行了内部验证。此外，免疫细胞类型浸润比共识分子亚型（CMS）和其他基于表达的生物标志物更能预测疾病复发（免疫AIC：238.1-238.9；CMS-AIC：241.0）。这些数据表明，转录组衍生的免疫谱是CRC复发的预后指标，先天性和适应性免疫细胞类型的量化可能作为预测预后以及指导疾病监测频率和方式的候选生物标志物。
