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Peer-reviewedCC BY 4.0Frontiers in Immunology

Spark-like T cell represents a novel functional state of CD8+T cells associated with anti-PD-1 immunotherapy response and clinical prognosis in non-small cell lung cancer

  • Zhuoqi Li1
  • Rui Li2
  • Feng Sun1
  • Chunyan Han1
  • Mei Tian3
  • Yinghua Song4
  • Wenhong Xu2
  • Lu Zhang1
  • Fujing Huang1
  • Xiao Wen1
  • Xiaoshu Yin1
  • Xiaoyan Lin2
1 more authors
  • Yuan Tian1
4 affiliations
  1. 1Department of Radiotherapy Oncology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine
  2. 2Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong First Medical University
  3. 3Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine
  4. 4Department of Respiratory and Critical Care Medicine, Shandong Second Provincial General Hospital (Shandong Provincial ENT Hospital)
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Abstract

Background: Spark-like T cells constitute a novel functional state of CD8 ⁺ T cells and have emerged as key drivers of immunotherapy response in preclinical models, yet their clinical relevance in non-small cell lung cancer (NSCLC) remains undefined.

Methods: Single-cell RNA sequencing (GSE207422), spatial transcriptomics (GSE271689), bulk RNA expression cohorts (TCGA-NSCLC, GSE37745, GSE41271, and GSE72094), and multiplex immunohistochemistry (mIHC) of a 100-patient cohort treated with anti-PD-1 were integrated to characterize Spark-like T cells and assess their clinical relevance. A 14-gene prognostic signature was constructed via LASSO-Cox regression.

Results: Spark-like T cells were significantly enriched in anti-PD-1 responders in the single-cell RNA sequencing cohort. mIHC validation in the 100-patient cohort confirmed that high Spark-like T cell intensity in tumors was independently associated with prolonged overall survival (log-rank test, p < 0.001) and partial response to anti-PD-1 therapy (p = 0.0075). Spatial transcriptomics indicated strong co-localization of Spark-like T cells with M1 macrophages (Spearman r = 0.524, p = 3.4 × 10 ⁻⁴² ), suggesting their spatial co-enrichment with pro-inflammatory myeloid cells. In silico knockout identified TNF, ENTPD1 (CD39), and IL2 as cooperative regulators of Spark-like T cell effector function. The 14-gene Spark-like T cell-related signature (VDAC1, ITGB1, GALNT2, SEMA7A, UBB, SLC7A5, FURIN, SNX9, PSMB2, CXCL13, TOX, PPM1M, CCND2, and CLNK) robustly predicted overall survival across all four independent cohorts and remained an independent prognostic factor after adjustment for age, sex, and tumor stage. High-risk patients exhibited an immune-excluded, oncogene-driven tumor microenvironment with reduced infiltration of CD8 ⁺ T cells.

Conclusions: Spark-like T cells are clinically relevant determinants of anti-PD-1 response in NSCLC. mIHC quantification and the 14-gene signature provide promising translational tools for patient stratification and risk assessment.

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Cite

BibTeXRIS
BibTeX
@article{li2026sparklike,
  title = {{Spark-like T cell represents a novel functional state of CD8+T cells associated with anti-PD-1 immunotherapy response and clinical prognosis in non-small cell lung cancer}},
  author = {Zhuoqi Li and Rui Li and Feng Sun and Chunyan Han and Mei Tian and Yinghua Song and Wenhong Xu and Lu Zhang and Fujing Huang and Xiao Wen and Xiaoshu Yin and Xiaoyan Lin and Yuan Tian},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1997857},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1997857/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Spark-like T cell represents a novel functional state of CD8+T cells associated with anti-PD-1 immunotherapy response and clinical prognosis in non-small cell lung cancer
AU  - Zhuoqi Li
AU  - Rui Li
AU  - Feng Sun
AU  - Chunyan Han
AU  - Mei Tian
AU  - Yinghua Song
AU  - Wenhong Xu
AU  - Lu Zhang
AU  - Fujing Huang
AU  - Xiao Wen
AU  - Xiaoshu Yin
AU  - Xiaoyan Lin
AU  - Yuan Tian
PY  - 2026
DA  - 2026/10/28
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1997857
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1997857/full
AB  - Background: Spark-like T cells constitute a novel functional state of CD8 ⁺ T cells and have emerged as key drivers of immunotherapy response in preclinical models, yet their clinical relevance in non-small cell lung cancer (NSCLC) remains undefined.  Methods: Single-cell RNA sequencing (GSE207422), spatial transcriptomics (GSE271689), bulk RNA expression cohorts (TCGA-NSCLC, GSE37745, GSE41271, and GSE72094), and multiplex immunohistochemistry (mIHC) of a 100-patient cohort treated with anti-PD-1 were integrated to characterize Spark-like T cells and assess their clinical relevance. A 14-gene prognostic signature was constructed via LASSO-Cox regression.  Results: Spark-like T cells were significantly enriched in anti-PD-1 responders in the single-cell RNA sequencing cohort. mIHC validation in the 100-patient cohort confirmed that high Spark-like T cell intensity in tumors was independently associated with prolonged overall survival (log-rank test, p < 0.001) and partial response to anti-PD-1 therapy (p = 0.0075). Spatial transcriptomics indicated strong co-localization of Spark-like T cells with M1 macrophages (Spearman r = 0.524, p = 3.4 × 10 ⁻⁴² ), suggesting their spatial co-enrichment with pro-inflammatory myeloid cells. In silico knockout identified TNF, ENTPD1 (CD39), and IL2 as cooperative regulators of Spark-like T cell effector function. The 14-gene Spark-like T cell-related signature (VDAC1, ITGB1, GALNT2, SEMA7A, UBB, SLC7A5, FURIN, SNX9, PSMB2, CXCL13, TOX, PPM1M, CCND2, and CLNK) robustly predicted overall survival across all four independent cohorts and remained an independent prognostic factor after adjustment for age, sex, and tumor stage. High-risk patients exhibited an immune-excluded, oncogene-driven tumor microenvironment with reduced infiltration of CD8 ⁺ T cells.  Conclusions: Spark-like T cells are clinically relevant determinants of anti-PD-1 response in NSCLC. mIHC quantification and the 14-gene signature provide promising translational tools for patient stratification and risk assessment.
SN  - 1664-3224
ER  -