Immune profiling identifies CD161+CD127+CD8+ T cells as a predictive biomarker for Anti-PD-L1 therapy response in the SCLC-I subtype
Abstract Background Advances in molecular subtype classification have improved the understanding of extensive-stage small cell lung cancer (ES-SCLC). However, immune landscape differences across ES-SCLC subtypes remain poorly defined. This study aimed to characterize ES-SCLC immune profiles and expl...
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BMC
2025-07-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06724-8 |
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| author | Jingjing Qu Wenjia Sun Yuekang Li Ziwan Cai Binggen Wu Qian Shen Lijun Chen Bo Wang Lixiong Ying Chenchai Xie Jing Zheng Jianya Zhou Jianying Zhou |
| author_facet | Jingjing Qu Wenjia Sun Yuekang Li Ziwan Cai Binggen Wu Qian Shen Lijun Chen Bo Wang Lixiong Ying Chenchai Xie Jing Zheng Jianya Zhou Jianying Zhou |
| author_sort | Jingjing Qu |
| collection | DOAJ |
| description | Abstract Background Advances in molecular subtype classification have improved the understanding of extensive-stage small cell lung cancer (ES-SCLC). However, immune landscape differences across ES-SCLC subtypes remain poorly defined. This study aimed to characterize ES-SCLC immune profiles and explore their association with response to immunotherapy. Methods Tumor samples from 135 patients with ES-SCLC were analyzed for molecular subtyping using immunohistochemical markers. Immune profiling of peripheral blood mononuclear cells was performed using cytometry by time-of-flight (CyTOF) and flow cytometry, and tumor tissues were assessed through multiplex immunofluorescence for immune cell subset characterization and distribution. Results Molecular subtyping of the 135 ES-SCLC cases identified 54.1%, 20.0%, 7.4%, and 18.5% as ASCL1-dominant, NEUROD1-dominant, POU2F3-dominant, and inflamed SCLC-I subtypes, respectively. CyTOF indicated a distinct enrichment of CD161+CD127+CD8+T cells in SCLC-I,with flow cytometry validating significantly higher proportions. These cells exhibited elevated cytotoxic markers (GZMB and GNLY) and reduced exhaustion markers (PD-1, TIGIT, and LAG-3) compared with those of other subtypes(P < 0.05). Multiplex immunofluorescence confirmed higher intratumoral infiltration of CD161+CD127+CD8+ T cells in SCLC-I. The intratumoral and peripheral levels of this subset were strongly correlated(r = 0.669, P < 0.0001). Patients with a CD161+CD127+CD8+ T/CD8+ T cell ratio of ≥ 2.7% had a significantly prolonged progression-free survival (PFS, 11.0 vs. 7.0 months, P = 0.0196). Conclusions The SCLC-I subtype exhibited a distinct immune profile characterized by enrichment of CD161+CD127+CD8+ T cells in both peripheral blood and tumor tissue, which was associated with PFS following anti–PD-L1 therapy. These findings highlight the significance of subtype-specific immune profiling and the potential of CD161+CD127+CD8+ T cells as a predictive biomarker to guide precision immunotherapy in ES-SCLC. |
| format | Article |
| id | doaj-art-df38adb60ea2418eb1b3506245ff34ea |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-df38adb60ea2418eb1b3506245ff34ea2025-08-20T03:45:34ZengBMCJournal of Translational Medicine1479-58762025-07-0123111710.1186/s12967-025-06724-8Immune profiling identifies CD161+CD127+CD8+ T cells as a predictive biomarker for Anti-PD-L1 therapy response in the SCLC-I subtypeJingjing Qu0Wenjia Sun1Yuekang Li2Ziwan Cai3Binggen Wu4Qian Shen5Lijun Chen6Bo Wang7Lixiong Ying8Chenchai Xie9Jing Zheng10Jianya Zhou11Jianying Zhou12Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of MedicineState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Pathology, The First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Pathology, The First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of MedicineAbstract Background Advances in molecular subtype classification have improved the understanding of extensive-stage small cell lung cancer (ES-SCLC). However, immune landscape differences across ES-SCLC subtypes remain poorly defined. This study aimed to characterize ES-SCLC immune profiles and explore their association with response to immunotherapy. Methods Tumor samples from 135 patients with ES-SCLC were analyzed for molecular subtyping using immunohistochemical markers. Immune profiling of peripheral blood mononuclear cells was performed using cytometry by time-of-flight (CyTOF) and flow cytometry, and tumor tissues were assessed through multiplex immunofluorescence for immune cell subset characterization and distribution. Results Molecular subtyping of the 135 ES-SCLC cases identified 54.1%, 20.0%, 7.4%, and 18.5% as ASCL1-dominant, NEUROD1-dominant, POU2F3-dominant, and inflamed SCLC-I subtypes, respectively. CyTOF indicated a distinct enrichment of CD161+CD127+CD8+T cells in SCLC-I,with flow cytometry validating significantly higher proportions. These cells exhibited elevated cytotoxic markers (GZMB and GNLY) and reduced exhaustion markers (PD-1, TIGIT, and LAG-3) compared with those of other subtypes(P < 0.05). Multiplex immunofluorescence confirmed higher intratumoral infiltration of CD161+CD127+CD8+ T cells in SCLC-I. The intratumoral and peripheral levels of this subset were strongly correlated(r = 0.669, P < 0.0001). Patients with a CD161+CD127+CD8+ T/CD8+ T cell ratio of ≥ 2.7% had a significantly prolonged progression-free survival (PFS, 11.0 vs. 7.0 months, P = 0.0196). Conclusions The SCLC-I subtype exhibited a distinct immune profile characterized by enrichment of CD161+CD127+CD8+ T cells in both peripheral blood and tumor tissue, which was associated with PFS following anti–PD-L1 therapy. These findings highlight the significance of subtype-specific immune profiling and the potential of CD161+CD127+CD8+ T cells as a predictive biomarker to guide precision immunotherapy in ES-SCLC.https://doi.org/10.1186/s12967-025-06724-8SCLC molecular subtypesCD161+CD127+CD8+ T cellsImmune profilingSurvival outcomeCyTOF |
| spellingShingle | Jingjing Qu Wenjia Sun Yuekang Li Ziwan Cai Binggen Wu Qian Shen Lijun Chen Bo Wang Lixiong Ying Chenchai Xie Jing Zheng Jianya Zhou Jianying Zhou Immune profiling identifies CD161+CD127+CD8+ T cells as a predictive biomarker for Anti-PD-L1 therapy response in the SCLC-I subtype Journal of Translational Medicine SCLC molecular subtypes CD161+CD127+CD8+ T cells Immune profiling Survival outcome CyTOF |
| title | Immune profiling identifies CD161+CD127+CD8+ T cells as a predictive biomarker for Anti-PD-L1 therapy response in the SCLC-I subtype |
| title_full | Immune profiling identifies CD161+CD127+CD8+ T cells as a predictive biomarker for Anti-PD-L1 therapy response in the SCLC-I subtype |
| title_fullStr | Immune profiling identifies CD161+CD127+CD8+ T cells as a predictive biomarker for Anti-PD-L1 therapy response in the SCLC-I subtype |
| title_full_unstemmed | Immune profiling identifies CD161+CD127+CD8+ T cells as a predictive biomarker for Anti-PD-L1 therapy response in the SCLC-I subtype |
| title_short | Immune profiling identifies CD161+CD127+CD8+ T cells as a predictive biomarker for Anti-PD-L1 therapy response in the SCLC-I subtype |
| title_sort | immune profiling identifies cd161 cd127 cd8 t cells as a predictive biomarker for anti pd l1 therapy response in the sclc i subtype |
| topic | SCLC molecular subtypes CD161+CD127+CD8+ T cells Immune profiling Survival outcome CyTOF |
| url | https://doi.org/10.1186/s12967-025-06724-8 |
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