Hissong Erika, Bhinder Bhavneet, Kim Junbum, Ohara Kentaro, Ravichandran Hiranmayi, Assaad Majd Al, Elsoukkary Sarah, Shusterman Michael, Khan Uqba, Eng Kenneth Wha, Bareja Rohan, Manohar Jyothi, Sigouros Michael, Rendeiro Andre F, Jessurun Jose, Ocean Allyson J, Sboner Andrea, Elemento Olivier, Mosquera Juan Miguel, Shah Manish A
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, 525 E 68th St, New York, NY 10065, USA; Englander Institute for Precision Medicine, Weill Cornell Medicine and New York Presbyterian, 413 E 69th St, New York, NY 10021, USA.
Englander Institute for Precision Medicine, Weill Cornell Medicine and New York Presbyterian, 413 E 69th St, New York, NY 10021, USA.
Pathol Res Pract. 2025 Sep;273:156150. doi: 10.1016/j.prp.2025.156150. Epub 2025 Jul 28.
Colorectal carcinoma (CRC) is a heterogeneous group of tumors with varying therapeutic response and prognosis, and evidence suggests the tumor immune microenvironment (TIME) plays a pivotal role. Using advanced molecular and spatial biology technologies, we aimed to evaluate the TIME in patients with CRC to determine whether specific characteristics of immune composition correlated with prognosis.
We identified primary and metastatic tumor samples from 31 consented patients, which were profiled with whole-exome sequencing and bulk RNA-seq. Immune cell deconvolution followed by gene set enrichment analysis and unsupervised clustering was performed. A subset of tumors underwent in situ analysis of the TIME spatial composition at single-cell resolution through Imaging Mass Cytometry.
Gene set enrichment analysis revealed two distinct groups of advanced CRC, one with an immune activated phenotype and the other with a suppressed immune microenvironment. The activated TIME phenotype contained increased Th1 cells, activated dendritic cells, tertiary lymphoid structures, and higher counts of CD8 + T cells whereas the inactive or suppressed TIME contained increased macrophages enriched for immunosuppressive M2 macrophages. Our findings were further supported by RNA-seq data analysis from the TCGA CRC database, in which the ratio of inactivated to activated dendritic cells within the CRC TIME correlated with a lower overall survival probability (HR 1.66, p = 0.007).
We identified distinct immunologic tumor microenvironments in colorectal cancer. Cancers harboring an activated TIME are associated with improved survival. Identifying key molecular drivers of the CRC TIME may offer opportunities to improve patient survival.
结直肠癌（CRC）是一组异质性肿瘤，其治疗反应和预后各不相同，有证据表明肿瘤免疫微环境（TIME）起着关键作用。我们旨在利用先进的分子和空间生物学技术评估CRC患者的TIME，以确定免疫组成的特定特征是否与预后相关。
我们从31名同意参与的患者中获取了原发性和转移性肿瘤样本，对其进行全外显子组测序和批量RNA测序分析。进行免疫细胞反卷积，随后进行基因集富集分析和无监督聚类。通过成像质谱流式细胞术对一部分肿瘤进行单细胞分辨率的TIME空间组成原位分析。
基因集富集分析揭示了晚期CRC的两个不同亚组，一组具有免疫激活表型，另一组具有免疫抑制微环境。激活的TIME表型包含更多的Th1细胞、活化的树突状细胞、三级淋巴结构以及更高数量的CD8 + T细胞，而不活跃或受抑制的TIME包含更多富含免疫抑制性M2巨噬细胞的巨噬细胞。我们的发现得到了TCGA CRC数据库RNA测序数据分析的进一步支持，其中CRC TIME内失活与活化树突状细胞的比例与较低的总生存概率相关（HR 1.66，p = 0.007）。
我们在结直肠癌中鉴定出了不同的免疫肿瘤微环境。具有激活的TIME的癌症与生存率提高相关。确定CRC TIME的关键分子驱动因素可能为改善患者生存提供机会。
