The final, formatted version of the article will be published soon.
ORIGINAL RESEARCH article
Front. Immunol.
Sec. T Cell Biology
Volume 16 - 2025 |
doi: 10.3389/fimmu.2025.1486329
Analysis of Tumor-infiltrating Exhausted T Cells Highlights IL-6 and PD1 Blockade as a Combined Immunotherapy Strategy for Non-Small Cell Lung Cancer
Provisionally accepted
Lu lu Zhang 1,2* Chun ying Ye 1* Ke xiao Sun 1* Jue Liao 1* Qin Liu 1* Yuan xi Guo 1* Hui zhi Yang 3*
Ratchada Cressey 4 Qing He 5*
Qing Yuan 1*- 1 Southwest Medical University, Luzhou, Sichuan, China
- 2 Nanjing Red Cross Blood Center, Nanjing, Jiangsu Province, China
- 3 The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- 4 Chiang Mai University, Chiang Mai, Thailand
- 5 West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
Abstract Objective Given the limitations of immunotherapy for treating non-small cell lung cancer (NSCLC), we investigated the phenotype and function of exhausted CD8+T cells, and analyzed a novel combination immunotherapy to restore the effector killing function of tumor-infiltrating CD8+T lymphocyte (TIL). Methods We examined the expression and function of immunosuppressive molecules on CD8+T cells of peripheral blood mononuclear cells (PBMCs) and TILs by using prospectively collected peripheral blood, pleural effusions, and tumor tissues from patients with NSCLC and correlated the results with clinical data. We then evaluated the effect of interleukin 6 (IL-6) stimulation on CD8+T cells. Finally, we assessed the effects of combined blockade of PD1 and IL-6 on macrophage recruitment in a zebrafish macrophage model and CD8+ T cell function and tumor growth in PBMC mouse model. Results The expression of exhaustion markers on CD8+ T cells was found to be notably higher in both tumor and paraneoplastic tissues compared to peripheral blood. Furthermore, the degree of CD8+ T cell exhaustion exhibited a progressive increase with proximity to the tumor. When CD8+ T cells from peripheral blood and tumor tissues of NSCLC patients were stimulated with IL-6, the expression level of exhaustion markers, especially PD1, was further elevated. In the in vitro experiment, the combined inhibition of IL-6 and PD1 substantially enhanced the effector killing function of CD8+ T cells in NSCLC pleural effusion samples. In a zebrafish macrophage model, combined blockade of IL-6 and PD1 enhanced the recruitment of macrophages. In PBMC humanized mouse model, combined blockade of IL-6 and PD1 enhanced the inhibition of tumor growth. Conclusion. Our data suggest that CD8+ T cells in NSCLC patients were in a state of exhaustion and combined blockade of IL-6 and PD1 to restore CD8+ T cell function to inhibit tumor growth may be an effective clinical strategy for the treatment of NSCLC.
Keywords: Exhausted CD8+T cells, Non-small cell lung cancer, Interleukin-6, PD1, Combined blockade
Received: 26 Aug 2024; Accepted: 20 Jan 2025.
Copyright: © 2025 Zhang, Ye, Sun, Liao, Liu, Guo, Yang, Cressey, He and Yuan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Lu lu Zhang, Southwest Medical University, Luzhou, Sichuan, China
Chun ying Ye, Southwest Medical University, Luzhou, Sichuan, China
Ke xiao Sun, Southwest Medical University, Luzhou, Sichuan, China
Jue Liao, Southwest Medical University, Luzhou, Sichuan, China
Qin Liu, Southwest Medical University, Luzhou, Sichuan, China
Yuan xi Guo, Southwest Medical University, Luzhou, Sichuan, China
Hui zhi Yang, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
Qing He, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
Qing Yuan, Southwest Medical University, Luzhou, Sichuan, China
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.