Identification of a cytokine-dominated immunosuppressive class in squamous cell lung carcinoma with implications for immunotherapy resistance

作者：Minglei Yang, Cheng-Hao Lin, Yanni Wang, Kang Chen, Haiyue Zhang, Weizhong Li · 发表于：Genome Medicine · 年份：2022 · DOI：10.1186/s13073-022-01079-x · 被引用次数：57 · 研究领域：Cancer Immunotherapy and Biomarkers、Ferroptosis and cancer prognosis、Immune cells in cancer

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. E...