Integrated analysis of single-cell and bulk RNA sequencing data reveals the association between hypoxic tumor cells and exhausted T cells in predicting immune therapy response

作者全名：Yan, Min; Wu, Ruixin; Fu, Han; Hu, Chao; Hao, Yanan; Zeng, Jie; Chen, Tong; Wang, Yingming; Wang, Yingying; Hu, Jing; Jin, Aishun

作者地址：[Yan, Min; Wu, Ruixin; Fu, Han; Hu, Chao; Hao, Yanan; Zeng, Jie; Chen, Tong; Wang, Yingming; Wang, Yingying; Jin, Aishun] Chongqing Med Univ, Sch Basic Med Sci, Dept Immunol, Chongqing 400010, Peoples R China; [Yan, Min; Jin, Aishun] Chongqing Med Univ, Chongqing Key Lab Basic & Translat Res Tumor Immun, Chongqing 400010, Peoples R China; [Hu, Jing] Childrens Hosp Philadelphia, Ctr Computat & Genom Med, Philadelphia, PA 19104 USA; [Hu, Jing] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

通信作者：Jin, AS (通讯作者)，Chongqing Med Univ, Sch Basic Med Sci, Dept Immunol, Chongqing 400010, Peoples R China.; Hu, J (通讯作者)，Childrens Hosp Philadelphia, Ctr Computat & Genom Med, Philadelphia, PA 19104 USA.

来源：COMPUTERS IN BIOLOGY AND MEDICINE

ESI学科分类：COMPUTER SCIENCE

WOS号：WOS:001202578800001

JCR分区：Q1

影响因子：7

年份：2024

卷号：171

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Cell interaction; Exhaustion; Hypoxia; Immunotherapy; Lung cancer; CXCR6

摘要：Continuous stimulation of tumor neoantigens and various cytokines in the tumor microenvironment leads to T cell dysfunction, but the specific mechanisms by which these key factors are distributed among different cell subpopulations and how they affect patient outcomes and treatment response are incompletely characterized. By integrating single-cell and bulk sequencing data of non-small cell lung cancer patients, we constructed a clinical outcome-associated T cell exhaustion signature. We discovered a significant association between the T cell exhaustion state and tumor cell hypoxia. Hypoxic malignant cells were significantly correlated with the proportion of exhausted T cells, and they co-occurred in patients at advanced stage. By analyzing the ligandreceptor interactions between these two cell states, we observed that T cells were recruited towards tumor cells through production of chemokines such as CXCL16-CXCR6 axis and CCL3/CCL4/CCL5-CCR5 axis. Based on 15 immune checkpoint blockade (ICB)-treatment cohorts, we constructed an interaction signature that can be used to predict the response to immune checkpoint blockade therapy. Among genes composed of the signature, CXCR6 alone has similarly high prediction efficacy (Area Under Curve (AUC) = 1, 0.89 and 0.73 for GSE126044, GSE135222 and GSE93157, respectively) with the signature and thus could serve as a potential biomarker for predicting immunotherapy response. Together, we have discovered and validated a significant association between exhausted T cells and hypoxic malignant cells, elucidating key interaction factors that significantly associated with response to immunotherapy.

基金机构：Postdoctoral Science Foundation of Chongqing Municipal Natural Science Foundation [CSTB2023NSCQ- BHX0152]; Chongqing Medical University Postdoctoral Scienti- fic Research Start -up Fund [R1066]

基金资助正文：This work is supported by the Postdoctoral Science Foundation of Chongqing Municipal Natural Science Foundation (CSTB2023NSCQ- BHX0152) and the Chongqing Medical University Postdoctoral Scienti- fic Research Start -up Fund (R1066) .