Precursor exhausted CD8+T cells in colorectal cancer tissues associated with patient's survival and immunotherapy responsiveness

Hao Huang; Junwei Ge; Zhang Fang; Shaoxian Wu; Hongwei Jiang; Yanyan Lang; Junjun Chen; Wenlu Xiao; Bin Xu; Yingting Liu; Lujun Chen; Xiao Zheng; Jingting Jiang

doi:10.3389/fimmu.2024.1362140

Precursor exhausted CD8⁺T cells in colorectal cancer tissues associated with patient's survival and immunotherapy responsiveness

Front Immunol. 2024 Mar 6:15:1362140. doi: 10.3389/fimmu.2024.1362140. eCollection 2024.

Authors

Hao Huang^{1

2

3}, Junwei Ge^{1

2

3}, Zhang Fang^{1

2

3}, Shaoxian Wu^{1

2

3}, Hongwei Jiang^{1

2

3}, Yanyan Lang^{1

2

3}, Junjun Chen^{1

2

3}, Wenlu Xiao^{1

2

3}, Bin Xu^{1

2

3}, Yingting Liu^{1

2

3}, Lujun Chen^{1

2

3}, Xiao Zheng^{1

2

3}, Jingting Jiang^{1

2

3}

Affiliations

¹ Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Jiangsu, Changzhou, China.
² Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Jiangsu, Changzhou, China.
³ Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Jiangsu, Changzhou, China.

Abstract

Exhausted CD8⁺T cells represent a distinct cellular lineage that emerges during both chronic infections and cancers. Recent studies have shown that persistent antigen exposure can drive the differentiation of precursor exhausted CD8⁺T cells, termed T_pex cells, which are characterized as TCF-1⁺PD-1⁺CD8⁺T cells. Elevated T_pex cell frequencies in the tumor microenvironment (TME) are associated with improved overall survival (OS) in cancer patients and heightened responsiveness to anti-PD-1 therapy. In our present study, we utilized multi-color immunohistochemistry (mIHC) to determine the localization and clinical implications of tumor-infiltrating T_pex cells within the TME of human colorectal cancer (CRC) tissues. We also conducted a multi-omics integrative analysis using single-cell RNA sequencing (scRNA-seq) data derived from both the murine MC38 tumor model and human CRC tissues. This analysis helped delineate the transcriptional and functional attributes of T_pex cells within the CRC TME. Furthermore, we employed spatial transcriptome sequencing data from CRC patients to investigate the interactions between T_pex cells and other immune cell subsets within the TME. In conclusion, our study not only established a method for T_pex cell detection using mIHC technology but also confirmed that assessing T_pex cells within the CRC TME could be indicative of patients' survival. We further uncovered the transcriptional and functional characteristics of T_pex cells in the TME and ascertained their pivotal role in the efficacy of immunotherapy against CRC.

Keywords: colorectal cancer; immunotherapy; multi-color immunohistochemistry; multi-omics; precursor exhausted CD8+T cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD8-Positive T-Lymphocytes
Cell Differentiation
Cell Lineage
Colorectal Neoplasms* / genetics
Colorectal Neoplasms* / therapy
Humans
Immunotherapy*
Mice
Tumor Microenvironment

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. The present study was supported by the National Natural Science Foundation of China (82172689 and 32270955), the Key R&D Project of Jiangsu Province (BE2022721 and BE2022719), the Natural Science Foundation of Jiangsu Province (BK20211065), the China Postdoctoral Science Foundation (2021M700547). This work was also supported by the Changzhou Clinical Medical Center and Outstanding Talent of Changzhou “The 14th Five-Year Plan” High-Level Health Talents Training Project, the Science and Technology Support Plan (Social Development) Project of Changzhou (CE20235058).