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

Authors

Jean-Philippe Guegan, Benjamin Bonhomme, Florent Peyraud, Christophe Rey, Sophie Cousin, Mihaela Aldea, Fabrice Barlesi, Benjamin Besse, David Planchard, Natalie Karpinich, Jaegil Kim, Racha Cheikh, Sapna Yadavilli, Alban Bessede, Antoine Italiano

Published in

Signal transduction and targeted therapy. Volume 11. Issue 1. Oct 26, 2026. Epub Oct 26, 2026.

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.

PMID:
42966824
Bibliographic data and abstract were imported from PubMed on 01 Nov 2026.

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