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Updated: Jun 5, 2025
Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
Multi-omic profiling highlights factors associated with resistance to immuno-chemotherapy in non-small-cell lung
Yilv Yan1, Dongqing Sun2,3, Junjie Hu1
1Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
Abstract:
Although immune checkpoint blockade (ICB) therapies have shifted the treatment paradigm for non-small-cell lung cancer (NSCLC), many patients remain resistant. Here we characterize the tumor cell states and spatial cellular compositions of the NSCLC tumor microenvironment (TME) by analyzing single-cell transcriptomes of 232,080 cells and spatially resolved transcriptomes of tumors from 19 patients before and after ICB-chemotherapy. We find that tumor cells and secreted phosphoprotein 1-positive macrophages interact with collagen type XI alpha 1 chain-positive cancer-associated fibroblasts to stimulate the deposition and entanglement of collagen fibers at tumor boundaries, obstructing T cell infiltration and leading to poor prognosis. We also reveal distinct states of tertiary lymphoid structures (TLSs) in the TME. Activated TLSs are associated with improved prognosis, whereas a hypoxic microenvironment appears to suppress TLS development and is associated with poor prognosis. Our study provides novel insights into different cellular and molecular components corresponding to NSCLC ICB-chemotherapeutic responsiveness, which will benefit future individualized immuno-chemotherapy.
Insights
Immune checkpoint blockade (ICB) resistance in non-small-cell lung cancer (NSCLC) is linked to collagen deposition by tumor cells and macrophages, hindering T cell entry. Activated tertiary lymphoid structures (TLSs) improve outcomes, while hypoxia worsens prognosis.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Immune checkpoint blockade (ICB) has revolutionized non-small-cell lung cancer (NSCLC) treatment.
- However, a significant portion of patients exhibit resistance to ICB therapies.
- Understanding the tumor microenvironment (TME) is crucial for overcoming resistance.
Purpose of the Study:
- To characterize tumor cell states and spatial cellular compositions in the NSCLC TME.
- To identify factors contributing to ICB resistance and responsiveness.
- To provide insights for individualized immuno-chemotherapy strategies.
Main Methods:
- Analysis of single-cell transcriptomes from 232,080 cells.
- Analysis of spatially resolved transcriptomes from 19 NSCLC patients.
- Assessment of TME cellular composition before and after ICB-chemotherapy.
Main Results:
- Tumor cells and SPP1+ macrophages interact with COL11A1+ fibroblasts, promoting collagen deposition that impedes T cell infiltration.
- Distinct states of tertiary lymphoid structures (TLSs) were identified in the TME.
- Activated TLSs correlate with improved prognosis, whereas a hypoxic TME suppresses TLS development and is linked to poor prognosis.
Conclusions:
- Specific cellular interactions and collagen entanglement at tumor boundaries contribute to ICB resistance in NSCLC.
- The state of TLSs and the presence of hypoxia are critical determinants of patient prognosis.
- These findings offer novel targets for enhancing ICB efficacy in NSCLC.
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