Analysis of tumor-infiltrating exhausted T cells highlights IL-6 and PD1 blockade as a combined immunotherapy strategy for non-small cell lung cancer
ObjectiveGiven 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).Me...
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1486329/full |
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| author | Lulu Zhang Lulu Zhang Xiyuan Guo Xiyuan Guo Xiaoke Sun Jue Liao Qin Liu Yingchun Ye Zhihui Yang Ratchada Cressey Qing He Qing Yuan Qing Yuan |
| author_facet | Lulu Zhang Lulu Zhang Xiyuan Guo Xiyuan Guo Xiaoke Sun Jue Liao Qin Liu Yingchun Ye Zhihui Yang Ratchada Cressey Qing He Qing Yuan Qing Yuan |
| author_sort | Lulu Zhang |
| collection | DOAJ |
| description | ObjectiveGiven 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).MethodsWe 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 humanized mouse model.ResultsThe 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 macrophage-labeled zebrafish 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.ConclusionOur 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. |
| format | Article |
| id | doaj-art-b17d97627ffe41089a4256e32323d32c |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-b17d97627ffe41089a4256e32323d32c2025-02-11T06:59:53ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-02-011610.3389/fimmu.2025.14863291486329Analysis of tumor-infiltrating exhausted T cells highlights IL-6 and PD1 blockade as a combined immunotherapy strategy for non-small cell lung cancerLulu Zhang0Lulu Zhang1Xiyuan Guo2Xiyuan Guo3Xiaoke Sun4Jue Liao5Qin Liu6Yingchun Ye7Zhihui Yang8Ratchada Cressey9Qing He10Qing Yuan11Qing Yuan12Public Center of Experimental Technology, The School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, ChinaBlood Distribution Department Nanjing Red Cross Blood Center, Nanjing, Jiangsu, ChinaPublic Center of Experimental Technology, The School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, ChinaDivision of Clinical Chemistry, Department of Medical Technology, Faculty of Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, ThailandKey Laboratory of Medical Electrophysiology of the Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, ChinaPublic Center of Experimental Technology, The School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, ChinaPublic Center of Experimental Technology, The School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, ChinaPublic Center of Experimental Technology, The School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, ChinaDepartment of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, ChinaDivision of Clinical Chemistry, Department of Medical Technology, Faculty of Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, ThailandDepartment of Head And Neck Oncology, West China Hospital of Sichuan University, Chengdu, Sichuan, ChinaPublic Center of Experimental Technology, The School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, ChinaInstitute of Nuclear Medicine, Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou, Sichuan, ChinaObjectiveGiven 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).MethodsWe 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 humanized mouse model.ResultsThe 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 macrophage-labeled zebrafish 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.ConclusionOur 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.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1486329/fullexhausted CD8+T cellsnon-small cell lung cancerinterleukin-6PD1combined blockade |
| spellingShingle | Lulu Zhang Lulu Zhang Xiyuan Guo Xiyuan Guo Xiaoke Sun Jue Liao Qin Liu Yingchun Ye Zhihui Yang Ratchada Cressey Qing He Qing Yuan Qing Yuan Analysis of tumor-infiltrating exhausted T cells highlights IL-6 and PD1 blockade as a combined immunotherapy strategy for non-small cell lung cancer Frontiers in Immunology exhausted CD8+T cells non-small cell lung cancer interleukin-6 PD1 combined blockade |
| title | Analysis of tumor-infiltrating exhausted T cells highlights IL-6 and PD1 blockade as a combined immunotherapy strategy for non-small cell lung cancer |
| title_full | Analysis of tumor-infiltrating exhausted T cells highlights IL-6 and PD1 blockade as a combined immunotherapy strategy for non-small cell lung cancer |
| title_fullStr | Analysis of tumor-infiltrating exhausted T cells highlights IL-6 and PD1 blockade as a combined immunotherapy strategy for non-small cell lung cancer |
| title_full_unstemmed | Analysis of tumor-infiltrating exhausted T cells highlights IL-6 and PD1 blockade as a combined immunotherapy strategy for non-small cell lung cancer |
| title_short | Analysis of tumor-infiltrating exhausted T cells highlights IL-6 and PD1 blockade as a combined immunotherapy strategy for non-small cell lung cancer |
| title_sort | analysis of tumor infiltrating exhausted t cells highlights il 6 and pd1 blockade as a combined immunotherapy strategy for non small cell lung cancer |
| topic | exhausted CD8+T cells non-small cell lung cancer interleukin-6 PD1 combined blockade |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1486329/full |
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