Spatially resolved transcriptomics reveal the determinants of primary resistance to immunotherapy in NSCLC with mature tertiary lymphoid structures.
retrospective_cohort · Level III
Where this comes from
- Record sourced from PubMed, PMID 39909044.
- Also identified by DOI 10.1016/j.xcrm.2025.101934 and PMC identifier 11866545.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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<sup>+</sup> T cell exhaustion, and increased regulatory CD4<sup>+</sup> 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.
Medical subject headings
- Carcinoma, Non-Small-Cell Lung
- Drug Resistance, Neoplasm
- Immunotherapy
- Lung Neoplasms
- Tertiary Lymphoid Structures
- Transcriptome