Skip to content
DraconiticResearch
Search Sources API
197,688 studies31 sourcesUpdated 35 min ago
Peer-reviewedCC BY-NC-ND 4.0Signal Transduction and Targeted Therapy

Spatial transcriptomics identifies tumor-intrinsic and stromal programs associated with immune exclusion in NSCLC

  • Jean-Philippe Guegan1
  • Benjamin Bonhomme2
  • Florent Peyraud3
  • Christophe Rey1
  • Sophie Cousin3
  • Mihaela Aldea4
  • Fabrice Barlesi4
  • Benjamin Besse4
  • David Planchard4
  • Natalie Karpinich5
  • Jaegil Kim6
  • Racha Cheikh7
3 more authors
  • Sapna Yadavilli8
  • Alban Bessede1
  • Antoine Italiano9,10
10 affiliations
  1. 1Explicyte, Bordeaux, France
  2. 2Department of Pathology, Institut Bergonié, Bordeaux, France
  3. 3Department of Medicine, Institut Bergonié, Bordeaux, France
  4. 4Gustave Roussy, Department of Medicine, Villejuif, France
  5. 5GSK, Collegeville, Pennsylvania USA
  6. 6GSK, Brookline, Massachusetts USA
  7. 7GSK, Mississauga, Ontario Canada
  8. 8GSK, Philadelphia, Pennsylvania USA
  9. 9Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, 94270 France
  10. 10DITEP, Gustave Roussy and University Paris Saclay, Villejuif, 94805 France
Read full textPDFDOICite

Abstract

Immune checkpoint blockade (ICB) has reshaped the treatment of advanced non-small cell lung cancer (NSCLC), yet durable benefit remains limited to a subset of patients. One major pattern of resistance is immune exclusion, in which CD8+ T cells accumulate in stromal regions but fail to penetrate tumor nests. Here, using discovery and non-overlapping internal validation cohorts of ICB-treated NSCLC patients, we show that spatial CD8+ T-cell exclusion is associated with lower objective response rates and shorter progression-free survival. To characterize the molecular programs linked to this phenotype, we integrated GeoMx spatial transcriptomics, bulk transcriptomic profiling, TCR-probe expression analysis, multiplex immunohistofluorescence, and single-cell spatial neighborhood analyses. Compared with infiltrated tumors, immune-excluded tumors showed reduced expression of genes encoding antigen-presentation machinery in the tumor compartment, including HLA class I genes and TAP1, with an altered relationship between IFN-γ-associated transcriptional signals and expression of antigen-presentation machinery. At the stromal level, excluded tumors were enriched for myofibroblastic cancer-associated fibroblast programs and peri-epithelial collagen-rich architecture, whereas infiltrated tumors displayed immune-supportive stromal signatures. CD8-enriched regions from excluded tumors showed reduced metabolic activation and lower TCR-probe expression diversity, without a marked increase in canonical exhaustion markers. These findings provide an integrated, compartment-resolved description of tumor-intrinsic and stromal features associated with immune exclusion in NSCLC and support further evaluation of spatial immune contexture as a complementary biomarker in ICB-treated patients.

Related

  1. Deep Learning-Based Spatial Profiling Identifies MET-Associated Immune Exclusion and Therapeutic Vulnerability Underlying Racial Disparities in Head and Neck Cancer
    Xinyu Cui, Fanghui Chen, Ashley McCook-Veal +7
    medRxivPreprintCC BY-NC-NDFull textOncologymedRxivPMC
  2. High-Resolution Spatial Transcriptomics Reveals Interferon-Associated Immune Niches and Antigen Presentation Programs in Inclusion Body Myositis
    S. de Haan, C. van Andel, L. Heezen +5
    medRxivPreprintCC BY-NC-NDFull textEpidemiology & public healthmedRxiv
  3. Spatial multi-omics and single-cell transcriptomics uncover senescence-associated cellular programs during colon adenoma to cancer progression
    M. Yu, Y. Xie, L. Allen +11
    bioRxivPreprintCC BYFull textOncologybioRxiv
  4. Cross-dataset transcriptomics–proteomics analysis identifies Tlr2, Anxa5, and Grin2a as candidate mouse-brain signatures associated with chronic cerebral hypoperfusion
    Xiang Fan, Meng-Yu Zhong, Huan Liu +6
    Frontiers in neurologyPeer-reviewedCC BYFull textNeurologyEurope PMCCrossref
  5. Spatial transcriptomics reveals tumour cell-intrinsic and microenvironmental features associated with survival in high-grade serous ovarian carcinoma
    M. A. A. K. Khan, W. Lin, E. Denisenko +7
    bioRxivPreprintCC BY-NC-NDFull textOncologybioRxiv

Cite

BibTeXRIS
BibTeX
@article{guegan2026spatial,
  title = {{Spatial transcriptomics identifies tumor-intrinsic and stromal programs associated with immune exclusion in NSCLC}},
  author = {Jean-Philippe Guegan and Benjamin Bonhomme and Florent Peyraud and Christophe Rey and Sophie Cousin and Mihaela Aldea and Fabrice Barlesi and Benjamin Besse and David Planchard and Natalie Karpinich and Jaegil Kim and Racha Cheikh and Sapna Yadavilli and Alban Bessede and Antoine Italiano},
  journal = {Signal Transduction and Targeted Therapy},
  year = {2026},
  month = oct,
  doi = {10.1038/s41392-026-02980-2},
  url = {https://doi.org/10.1038/s41392-026-02980-2},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Spatial transcriptomics identifies tumor-intrinsic and stromal programs associated with immune exclusion in NSCLC
AU  - Jean-Philippe Guegan
AU  - Benjamin Bonhomme
AU  - Florent Peyraud
AU  - Christophe Rey
AU  - Sophie Cousin
AU  - Mihaela Aldea
AU  - Fabrice Barlesi
AU  - Benjamin Besse
AU  - David Planchard
AU  - Natalie Karpinich
AU  - Jaegil Kim
AU  - Racha Cheikh
AU  - Sapna Yadavilli
AU  - Alban Bessede
AU  - Antoine Italiano
PY  - 2026
DA  - 2026/10/26
JO  - Signal Transduction and Targeted Therapy
DO  - 10.1038/s41392-026-02980-2
UR  - https://doi.org/10.1038/s41392-026-02980-2
AB  - Immune checkpoint blockade (ICB) has reshaped the treatment of advanced non-small cell lung cancer (NSCLC), yet durable benefit remains limited to a subset of patients. One major pattern of resistance is immune exclusion, in which CD8+ T cells accumulate in stromal regions but fail to penetrate tumor nests. Here, using discovery and non-overlapping internal validation cohorts of ICB-treated NSCLC patients, we show that spatial CD8+ T-cell exclusion is associated with lower objective response rates and shorter progression-free survival. To characterize the molecular programs linked to this phenotype, we integrated GeoMx spatial transcriptomics, bulk transcriptomic profiling, TCR-probe expression analysis, multiplex immunohistofluorescence, and single-cell spatial neighborhood analyses. Compared with infiltrated tumors, immune-excluded tumors showed reduced expression of genes encoding antigen-presentation machinery in the tumor compartment, including HLA class I genes and TAP1, with an altered relationship between IFN-γ-associated transcriptional signals and expression of antigen-presentation machinery. At the stromal level, excluded tumors were enriched for myofibroblastic cancer-associated fibroblast programs and peri-epithelial collagen-rich architecture, whereas infiltrated tumors displayed immune-supportive stromal signatures. CD8-enriched regions from excluded tumors showed reduced metabolic activation and lower TCR-probe expression diversity, without a marked increase in canonical exhaustion markers. These findings provide an integrated, compartment-resolved description of tumor-intrinsic and stromal features associated with immune exclusion in NSCLC and support further evaluation of spatial immune contexture as a complementary biomarker in ICB-treated patients.
SN  - 2095-9907
SN  - 2059-3635
ER  -