High CD8+tumor-infiltrating lymphocytes indicate severe exhaustion and poor prognosis in angioimmunoblastic T-cell lymphoma

Qiqi Zhu; Yiming Yang; Xueqin Deng; Ningning Chao; Zihang Chen; Yunxia Ye; Wenyan Zhang; Weiping Liu; Sha Zhao

doi:10.3389/fimmu.2023.1228004

High CD8⁺tumor-infiltrating lymphocytes indicate severe exhaustion and poor prognosis in angioimmunoblastic T-cell lymphoma

Front Immunol. 2023 Sep 15:14:1228004. doi: 10.3389/fimmu.2023.1228004. eCollection 2023.

Authors

Qiqi Zhu^{1

2}, Yiming Yang^{2

3}, Xueqin Deng¹, Ningning Chao⁴, Zihang Chen¹, Yunxia Ye¹, Wenyan Zhang¹, Weiping Liu¹, Sha Zhao¹

Affiliations

¹ Department of Pathology, West China Hospital, Sichuan University, Chengdu, China.
² Department of Pathology, North Sichuan Medical College, Affiliated Hospital of North Sichuan Medical College, Nanchong, China.
³ Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong, China.
⁴ Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China.

Abstract

Background: Exhaustion of CD8⁺ tumor-infiltrating lymphocytes (TILs), characterized by the overexpression of immune checkpoints (IC), is a major impediment to anti-tumor immunity. However, the exhaustion status of CD8⁺TILs in angioimmunoblastic T cell lymphoma (AITL) remains unclear. Therefore, we aimed to elucidate the exhaustion status of CD8⁺TILs in AITL and its influence on prognosis.

Methods: The correlation between CD8⁺TILs and IC expression in AITL was analyzed using single-cell RNA sequencing (n = 2), flow cytometry (n = 20), and RNA sequencing (n = 20). Biological changes related to CD8⁺TILs exhaustion at different cytotoxic T lymphocyte (CTL) levels (mean expression levels of CD8A, CD8B, GZMA, GZMB, and PRF1) in AITL were evaluated using RNA sequencing (n = 20) and further validated using the GEO dataset (n = 51). The impact of CD8 protein expression and CTL levels on patient prognosis was analyzed using flow cytometry and RNA sequencing, respectively.

Results: Our findings demonstrated that the higher the infiltration of CD8⁺TILs, the higher was the proportion of exhausted CD8⁺TILs characterized by the overexpression of multiple IC. This was accompanied by extensive exhaustion-related biological changes, which suggested severe exhaustion in CD8⁺TILs and may be one of the main reasons for the poor prognosis of patients with high CD8⁺TILs and CTL.

Conclusion: Our study comprehensively reveals the exhaustion status of CD8⁺TILs and their potential negative impact on AITL prognosis, which facilitates further mechanistic studies and is valuable for guiding immunotherapy strategies.

Keywords: CD8 + tumor-infiltrating lymphocytes; angioimmunoblastic T-cell lymphoma; exhaustion; immune checkpoint; prognosis; single-cell RNA sequencing; therapy.

Publication types

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

MeSH terms

CD8-Positive T-Lymphocytes*
Humans
Lymphocytes, Tumor-Infiltrating*
Lymphoma, T-Cell* / diagnosis
Lymphoma, T-Cell* / immunology
Prognosis
T-Lymphocytes, Cytotoxic

Grants and funding

This study was supported by 1·3·5 project for disciplines of excellence–Clinical Research Incubation Project, West China Hospital, Sichuan University (2021HXFH027) and Sichuan Science and Technology Program (2023NSFSC0718).