Spatial interaction of tumor cells and regulatory T cells correlates with survival in non-small cell lung cancer

CD8型 肿瘤微环境 医学 肺癌 FOXP3型 川地68 多路复用 免疫系统 病理 单变量分析 组织微阵列 免疫组织化学 癌症研究 内科学 生物 免疫学 多元分析 生物信息学
作者
Souptik Barua,Penny Fang,Amrish Sharma,Junya Fujimoto,Ignacio I. Wistuba,Arvind Rao,Steven H. Lin
出处
期刊:Lung Cancer [Elsevier BV]
卷期号:117: 73-79 被引量:155
标识
DOI:10.1016/j.lungcan.2018.01.022
摘要

Objectives To determine the prognostic significance of spatial proximity of lung cancer cells and specific immune cells in the tumor microenvironment. Materials and methods We probed formalin-fixed, paraffin-embedded (FFPE) tissue microarrays using a novel tyramide signal amplification multiplexing technique labelling CD8, CD4, Foxp3, and CD68+ cells. Each multiplex stained immunohistochemistry slide was digitally processed by Vectra INFORMS software, and an X- and Y-coordinate assigned to each labeled cell type. The abundance and spatial location of each cell type and their proximity to one another was analyzed using a novel application of the G-cross spatial distance distribution method which computes the probability of finding at least one immune cell of any given type within a rμm radius of a tumor cell. Cox proportional hazards multiple regression was used for multivariate analysis of the influence of proximity of lymphocyte types. Results Pathologic tumor specimens from 120 NSCLC patients with pathologic tumor stage I–III disease were analyzed. On univariate analysis, age (P = .0007) and number of positive nodes (P = .0014) were associated with overall survival. Greater area under the curve (AUC) of the G-cross function for tumor cell-Treg interactions was significantly associated with worse survival adjusting for age and number of positive nodes (HR 1.52 (1.11–2.07), P = .009). Greater G-cross AUC for T-reg-CD8 was significantly associated with better survival adjusting for age and number of positive lymph nodes (HR 0.96 (0.92–0.99), P = .042). Conclusion Increased infiltration of regulatory T cells into core tumor regions is an independent predictor of worse overall survival in NSCLC. However, increased infiltration of CD8+ cytotoxic T cells among regulatory T cells seems to mitigate this effect and was significantly associated with better survival. Validation of the G-cross method of measuring spatial proximity between tumor and immune cell types and exploration of its use as a prognostic factor in lung cancer treatment is warranted.
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