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Background <p>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.</p> Methods <p>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.</p> Results <p>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<sup>+</sup>CD127<sup>+</sup>CD8<sup>+</sup>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(<i>P</i> &lt; 0.05). Multiplex immunofluorescence confirmed higher intratumoral infiltration of CD161<sup>+</sup>CD127<sup>+</sup>CD8<sup>+</sup> T cells in SCLC-I. The intratumoral and peripheral levels of this subset were strongly correlated(<i>r</i> = 0.669, <i>P</i> &lt; 0.0001). Patients with a CD161<sup>+</sup>CD127<sup>+</sup>CD8<sup>+</sup> T/CD8<sup>+</sup> T cell ratio of ≥ 2.7% had a significantly prolonged progression-free survival (PFS, 11.0 vs. 7.0 months, <i>P</i> = 0.0196).</p> Conclusions <p>The SCLC-I subtype exhibited a distinct immune profile characterized by enrichment of CD161<sup>+</sup>CD127<sup>+</sup>CD8<sup>+</sup> 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<sup>+</sup>CD127<sup>+</sup>CD8<sup>+</sup> T cells as a predictive biomarker to guide precision immunotherapy in ES-SCLC.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月1日

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  • 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

摘要

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.