Immune profiling identifies CD161+CD127+CD8+ T cells as a predictive biomarker for Anti-PD-L1 therapy response in the
Jingjing Qu1,2, Wenjia Sun1,2, Yuekang Li1,2
1Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, China.
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.
