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Updated: May 29, 2025
Predictive Immune Modeling of Solid Tumors
Published on: February 25, 2020
Spatially resolved transcriptomics reveal the determinants of primary resistance to immunotherapy in NSCLC with
Florent Peyraud1, Jean-Philippe Guégan2, Christophe Rey2
1Department of Medicine, Institut Bergonié, Bordeaux, France; Faculty of Medicine, University of Bordeaux, Bordeaux, France; Explicyte Immuno-Oncology, Bordeaux, France.
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+ 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.
Insights
Mature tertiary lymphoid structures (mTLSs) in non-small cell lung cancer (NSCLC) correlate with better outcomes. However, specific cancer-associated fibroblasts (CAFs) can cause resistance to immune checkpoint inhibitors (ICIs), suggesting new therapeutic targets.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Immune checkpoint inhibitors (ICIs) show variable effectiveness in non-small cell lung cancer (NSCLC).
- Mature tertiary lymphoid structures (mTLSs) in the tumor microenvironment (TME) are associated with improved outcomes in NSCLC patients treated with ICIs.
- The precise mechanisms underlying ICI response and resistance in mTLS-positive NSCLC remain incompletely understood.
Purpose of the Study:
- To investigate the role of mTLSs and associated cellular components in predicting response to ICIs in NSCLC.
- To identify specific cellular factors within the TME that mediate primary resistance to ICIs in mTLS-positive NSCLC.
- To explore novel therapeutic targets for enhancing ICI efficacy in NSCLC.
Main Methods:
- Comprehensive analysis of 509 ICI-treated NSCLC patients from the Bergonié Institute Profiling (BIP) study.
- Utilized spatial transcriptomics and multiplex immunofluorescence (mIF) for detailed TME analysis.
- Correlated clinical outcomes with the presence of mTLSs, PD-L1 expression, and genomic features.
Main Results:
- mTLS presence significantly correlates with improved clinical outcomes in NSCLC, independent of PD-L1 expression and genomic profiles.
- Two distinct subsets of cancer-associated fibroblasts (CAFs) were identified as key mediators of primary resistance to ICIs in mTLS-positive NSCLC.
- These CAFs are linked to immune exclusion, CD8+ T cell exhaustion, and increased regulatory CD4+ T cell infiltration, creating an immunosuppressive TME.
Conclusions:
- Specific CAF subsets play a critical role in hindering ICI effectiveness in NSCLC.
- Targeting these identified CAF subsets presents a promising strategy to overcome primary resistance and enhance immunotherapy efficacy in NSCLC.
- Understanding the intricate TME landscape is crucial for optimizing cancer immunotherapy.
