Cancer Immunotherapy and Biomarkers
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It is shown that two distinct subsets of cancer-associated fibroblasts (CAFs) are essential factors in mediating primary resistance to ICIs in mTLS-positive NSCLC, underscoring an immunosuppressive TME.
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Effectiveness of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) has been linked to the presence of mature tertiary lymphoid structures (mTLSs) within the tumor microenvironment (TME). However, only a subset of mTLS-positive NSCLC derives benefit, thus highlighting the need to unravel ICI response determinants. The comprehensive analysis of ICI-treated patients with NSCLC (n = 509) from the Bergonié Institute Profiling (BIP) study (NCT02534649) reveals that the presence of mTLSs correlates with improved clinical outcomes, independently of programmed death ligand 1 (PD-L1) expression and genomic features. Employing spatial transcriptomics alongside multiplex immunofluorescence (mIF), we show that two distinct subsets of cancer-associated fibroblasts (CAFs) are essential factors in mediating primary resistance to ICIs in mTLS-positive NSCLC. These CAFs are associated with immune exclusion, CD8+ T cell exhaustion, and increased regulatory CD4+ T cell infiltration, underscoring an immunosuppressive TME. Our study highlights the pivotal role of specific CAF subsets in thwarting ICIs, proposing new therapeutic targets to enhance immunotherapy efficacy.
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@article{Peyraud2025Spatially,
title = {Spatially resolved transcriptomics reveal the determinants of primary resistance to immunotherapy in NSCLC with mature tertiary lymphoid structures},
author = {Florent Peyraud and Jean-Philippe Guégan and Christophe Rey and Oren Lara and Ophélie Odin and Marie Del Castillo and Lucile Vanhersecke and Jean‐Michel Coindre and Emma Clot and Maxime Brunet and Thomas Grellety and Angélique Tasseel and Sylvestre Le Moulec and Robert J. Johnston and Alban Bessede and Antoine Italiano},
journal = {Cell Reports Medicine},
year = {2025},
doi = {10.1016/j.xcrm.2025.101934},
url = {https://doi.org/10.1016/j.xcrm.2025.101934}
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