Spatial effects of infiltrating T cells on neighbouring cancer cells and prognosis in stage III CRC patients

IF 5.6 2区医学 Q1 ONCOLOGY

The Journal of Pathology Pub Date : 2024-08-02 DOI:10.1002/path.6327

Mohammadreza Azimi, Sanghee Cho, Emir Bozkurt, Elizabeth McDonough, Batuhan Kisakol, Anna Matveeva, Manuela Salvucci, Heiko Dussmann, Simon McDade, Canan Firat, Nil Urganci, Jinru Shia, Daniel B Longley, Fiona Ginty, Jochen HM Prehn

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引用次数: 0

Abstract

Colorectal cancer (CRC) is one of the most frequently occurring cancers, but prognostic biomarkers identifying patients at risk of recurrence are still lacking. In this study, we aimed to investigate in more detail the spatial relationship between intratumoural T cells, cancer cells, and cancer cell hallmarks as prognostic biomarkers in stage III colorectal cancer patients. We conducted multiplexed imaging of 56 protein markers at single-cell resolution on resected fixed tissue from stage III CRC patients who received adjuvant 5-fluorouracil (5FU)-based chemotherapy. Images underwent segmentation for tumour, stroma, and immune cells, and cancer cell ‘state’ protein marker expression was quantified at a cellular level. We developed a Python package for estimation of spatial proximity, nearest neighbour analysis focusing on cancer cell–T-cell interactions at single-cell level. In our discovery cohort (Memorial Sloan Kettering samples), we processed 462 core samples (total number of cells: 1,669,228) from 221 adjuvant 5FU-treated stage III patients. The validation cohort (Huntsville Clearview Cancer Center samples) consisted of 272 samples (total number of cells: 853,398) from 98 stage III CRC patients. While there were trends for an association between the percentage of cytotoxic T cells (across the whole cancer core), it did not reach significance (discovery cohort: p = 0.07; validation cohort: p = 0.19). We next utilised our region-based nearest neighbour approach to determine the spatial relationships between cytotoxic T cells, helper T cells, and cancer cell clusters. In both cohorts, we found that shorter distance between cytotoxic T cells, T helper cells, and cancer cells was significantly associated with increased disease-free survival. An unsupervised trained model that clustered patients based on the median distance between immune cells and cancer cells, as well as protein expression profiles, successfully classified patients into low-risk and high-risk groups (discovery cohort: p = 0.01; validation cohort: p = 0.003). © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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浸润 T 细胞对邻近癌细胞的空间影响与 III 期 CRC 患者的预后。

结直肠癌（CRC）是发病率最高的癌症之一，但目前仍缺乏识别复发风险患者的预后生物标志物。在这项研究中，我们旨在更详细地研究作为 III 期结直肠癌患者预后生物标志物的瘤内 T 细胞、癌细胞和癌细胞标志物之间的空间关系。我们对接受了基于 5 氟尿嘧啶（5FU）的辅助化疗的 III 期结直肠癌患者切除的固定组织进行了单细胞分辨率的 56 种蛋白质标记物的多重成像。对图像进行了肿瘤、基质和免疫细胞的分割，并在细胞水平上量化了癌细胞 "状态 "蛋白质标记物的表达。我们开发了一个 Python 软件包，用于估算空间邻近性和近邻分析，重点是单细胞水平的癌细胞-T 细胞相互作用。在我们的发现队列（纪念斯隆-凯特琳癌症中心样本）中，我们处理了来自 221 名经过 5FU 辅助治疗的 III 期患者的 462 份核心样本（细胞总数：1,669,228）。验证队列（亨茨维尔 Clearview 癌症中心样本）包括来自 98 名 III 期 CRC 患者的 272 份样本（细胞总数：853,398 个）。虽然细胞毒性 T 细胞的百分比（整个癌症核心）之间存在关联趋势，但未达到显著性（发现队列：P = 0.07；验证队列：P = 0.19）。接下来，我们利用基于区域的最近邻方法来确定细胞毒性 T 细胞、辅助性 T 细胞和癌细胞集群之间的空间关系。我们发现，在两个队列中，细胞毒性 T 细胞、T 辅助细胞和癌细胞之间的距离越短，无病生存率越高。根据免疫细胞和癌细胞之间的中位距离以及蛋白质表达谱对患者进行聚类的无监督训练模型成功地将患者分为低风险组和高风险组（发现队列：p = 0.01；验证队列：p = 0.003）。© 2024 作者。病理学杂志》由 John Wiley & Sons Ltd 代表大不列颠及爱尔兰病理学会出版。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

The Journal of Pathology 医学-病理学

CiteScore

14.10

自引率

1.40%

发文量

144

审稿时长

3-8 weeks

期刊介绍： The Journal of Pathology aims to serve as a translational bridge between basic biomedical science and clinical medicine with particular emphasis on, but not restricted to, tissue based studies. The main interests of the Journal lie in publishing studies that further our understanding the pathophysiological and pathogenetic mechanisms of human disease. The Journal of Pathology welcomes investigative studies on human tissues, in vitro and in vivo experimental studies, and investigations based on animal models with a clear relevance to human disease, including transgenic systems. As well as original research papers, the Journal seeks to provide rapid publication in a variety of other formats, including editorials, review articles, commentaries and perspectives and other features, both contributed and solicited.