Immune profiling identifies CD161+CD127+CD8+ T cells as a predictive biomarker for Anti-PD-L1 therapy response in the SCLC-I subtype

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

doi:10.1186/s12967-025-06724-8

Immune profiling identifies CD161⁺CD127⁺CD8⁺ T cells as a predictive biomarker for Anti-PD-L1 therapy response in the SCLC-I subtype

J Transl Med. 2025 Jul 1;23(1):711. doi: 10.1186/s12967-025-06724-8.

Authors

Jingjing Qu^#^{1

2}, Wenjia Sun^#^{1

2}, Yuekang Li^#^{1

2}, Ziwan Cai^{1

2}, Binggen Wu^{1

2}, Qian Shen^{1

2}, Lijun Chen³, Bo Wang⁴, Lixiong Ying⁴, Chenchai Xie¹, Jing Zheng^{1

2}, Jianya Zhou^{5

6}, Jianying Zhou^{1

2}

Affiliations

¹ Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, China.
² The Clinical Research Center for Respiratory Diseases of Zhejiang Province, Hangzhou, 310003, Zhejiang, China.
³ State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, China.
⁴ Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, China.
⁵ Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, China. zhoujy@zju.edu.cn.
⁶ The Clinical Research Center for Respiratory Diseases of Zhejiang Province, Hangzhou, 310003, Zhejiang, China. zhoujy@zju.edu.cn.

^# Contributed equally.

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.

Keywords: CD161+CD127+CD8+ T cells; CyTOF; Immune profiling; SCLC molecular subtypes; Survival outcome.

MeSH terms

Aged
B7-H1 Antigen* / antagonists & inhibitors
Biomarkers, Tumor* / metabolism
CD8-Positive T-Lymphocytes* / immunology
Female
Humans
Immunotherapy
Lung Neoplasms* / drug therapy
Lung Neoplasms* / immunology
Lung Neoplasms* / therapy
Male
Middle Aged
NK Cell Lectin-Like Receptor Subfamily B* / metabolism
Small Cell Lung Carcinoma* / drug therapy
Small Cell Lung Carcinoma* / immunology
Small Cell Lung Carcinoma* / pathology
Small Cell Lung Carcinoma* / therapy
Treatment Outcome

Substances

Biomarkers, Tumor
B7-H1 Antigen
NK Cell Lectin-Like Receptor Subfamily B

Grants and funding

LY23H160020/Natural Science Foundation of Zhejiang Province