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; 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.
Res Sq. 2024 Jul 25:rs.3.rs-4751101. doi: 10.21203/rs.3.rs-4751101/v1.
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 alterations in the 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 analysis of the TIME spatial composition at single-cell resolution through Imaging Mass 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 and a higher M2/M1 ratio. Our findings were further supported by RNA-seq data analysis from the TCGA CRC database, in which unsupervised clustering also identified two separate groups. The immunosuppressed CRC TIME had a lower overall survival probability (HR 1.66, p=0.007). This study supports the pertinent role of the CRC immune microenvironment in tumor progression and patient prognosis. We characterized the immune cell composition to better understand the complexity and vital role that immune activity states of the TIME play in determining patient outcome.
结直肠癌（CRC）是一组异质性肿瘤，具有不同的治疗反应和预后，有证据表明肿瘤免疫微环境（TIME）起着关键作用。我们利用先进的分子和空间生物学技术，旨在评估CRC患者的TIME，以确定免疫组成的特定改变是否与预后相关。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，并对其进行了全外显子组测序和批量RNA测序分析。随后进行免疫细胞反卷积，接着进行基因集富集分析和无监督聚类。对一部分肿瘤通过成像质谱流式细胞术在单细胞分辨率下分析TIME的空间组成。基因集富集分析揭示了晚期CRC的两个不同亚组，一个具有免疫激活表型，另一个具有免疫微环境抑制表型。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，而无活性或受抑制的TIME则包含更多的巨噬细胞和更高的M2/M1比值。我们的发现得到了来自TCGA CRC数据库的RNA测序数据分析的进一步支持，其中无监督聚类也识别出两个不同的亚组。免疫抑制的CRC TIME的总生存概率较低（HR 1.66，p = 0.007）。本研究支持了CRC免疫微环境在肿瘤进展和患者预后中的重要作用。我们对免疫细胞组成进行了特征分析，以更好地理解TIME的免疫活性状态在决定患者预后方面所起的复杂性和关键作用。
