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Author Spotlight: Enhancing Multicolor Fluorescence Localization in Lung Carcinoma Sample
Published on: November 21, 2023
Identification of a cytokine-dominated immunosuppressive class in squamous cell lung carcinoma with implications for
Minglei Yang1, Chenghao Lin1, Yanni Wang1
1Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
Background:
Immune checkpoint blockade (ICB) therapy has revolutionized the treatment of lung squamous cell carcinoma (LUSC). However, a significant proportion of patients with high tumour PD-L1 expression remain resistant to immune checkpoint inhibitors. To understand the underlying resistance mechanisms, characterization of the immunosuppressive tumour microenvironment and identification of biomarkers to predict resistance in patients are urgently needed.
Methods:
Our study retrospectively analysed RNA sequencing data of 624 LUSC samples. We analysed gene expression patterns from tumour microenvironment by unsupervised clustering. We correlated the expression patterns with a set of T cell exhaustion signatures, immunosuppressive cells, clinical characteristics, and immunotherapeutic responses. Internal and external testing datasets were used to validate the presence of exhausted immune status.
Results:
Approximately 28 to 36% of LUSC patients were found to exhibit significant enrichments of T cell exhaustion signatures, high fraction of immunosuppressive cells (M2 macrophage and CD4 Treg), co-upregulation of 9 inhibitory checkpoints (CTLA4, PDCD1, LAG3, BTLA, TIGIT, HAVCR2, IDO1, SIGLEC7, and VISTA), and enhanced expression of anti-inflammatory cytokines (e.g. TGFβ and CCL18). We defined this immunosuppressive group of patients as exhausted immune class (EIC). Although EIC showed a high density of tumour-infiltrating lymphocytes, these were associated with poor prognosis. EIC had relatively elevated PD-L1 expression, but showed potential resistance to ICB therapy. The signature of 167 genes for EIC prediction was significantly enriched in melanoma patients with ICB therapy resistance. EIC was characterized by a lower chromosomal alteration burden and a unique methylation pattern. We developed a web application ( http://lilab2.sysu.edu.cn/tex & http://liwzlab.cn/tex ) for researchers to further investigate potential association of ICB resistance based on our multi-omics analysis data.
Conclusions:
We introduced a novel LUSC immunosuppressive class which expressed high PD-L1 but showed potential resistance to ICB therapy. This comprehensive characterization of immunosuppressive tumour microenvironment in LUSC provided new insights for further exploration of resistance mechanisms and optimization of immunotherapy strategies.
Insights
A novel immunosuppressive class in lung squamous cell carcinoma (LUSC) exhibits high PD-L1 expression but resists immune checkpoint blockade (ICB) therapy. This finding aids in understanding resistance and optimizing ICB strategies for LUSC patients.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Immune checkpoint blockade (ICB) therapy has transformed lung squamous cell carcinoma (LUSC) treatment.
- A subset of LUSC patients with high PD-L1 expression shows resistance to ICB therapy.
- Understanding the immunosuppressive tumor microenvironment is crucial for overcoming ICB resistance.
Purpose of the Study:
- To characterize the immunosuppressive tumor microenvironment in LUSC.
- To identify biomarkers predicting resistance to ICB therapy.
- To define a novel patient subgroup associated with ICB resistance.
Main Methods:
- Retrospective analysis of RNA sequencing data from 624 LUSC samples.
- Unsupervised clustering to analyze gene expression patterns in the tumor microenvironment.
- Correlation of expression patterns with T cell exhaustion, immunosuppressive cells, clinical characteristics, and immunotherapeutic responses.
- Validation using internal and external datasets.
Main Results:
- Identified an exhausted immune class (EIC) in 28-36% of LUSC patients, characterized by T cell exhaustion, immunosuppressive cells (M2 macrophages, CD4 Tregs), co-upregulated checkpoints, and anti-inflammatory cytokines.
- EIC exhibits high PD-L1 expression but shows potential resistance to ICB therapy, despite high tumor-infiltrating lymphocytes.
- A 167-gene signature for EIC prediction was validated and associated with ICB resistance in melanoma.
- Developed a web application for exploring multi-omics data related to ICB resistance.
Conclusions:
- Introduced a novel immunosuppressive EIC in LUSC with high PD-L1 expression and potential ICB resistance.
- Comprehensive characterization of the LUSC immunosuppressive tumor microenvironment offers insights into resistance mechanisms.
- Findings pave the way for optimizing immunotherapy strategies in LUSC.
