Single-cell transcriptomics reveals ADRB1 as a key immune checkpoint regulating T cell exhaustion in lung cancer and its prognostic value in lung cancer.

Abstract

Lung cancer, LUAD, and LUSC are both among the leading causes of cancer-related deaths. T cell exhaustion within the tumor microenvironment compromises the immune response and limits the benefits of immune checkpoint therapy. Adrenergic signaling primarily through ADRB1 induces T cell exhaustion and immune suppression. ADRB1 + T cells have not yet been studied regarding their role in lung cancer progression or prognosis. scRNA-seq analysis for tumor and adjacent nontumor tissues from patients with LUAD and LUSC. Dimensionality reduction and clustering with Scanpy, followed by ssGSEA for adrenergic signaling activity. CNV was processed with inferCNV, and cell-to-cell communication was inferred via CellChat. Integration with TCGA bulk RNA-seq data enables prognostic modeling of ADRB1⁺ T cells. Kaplan-Meier survival analysis and univariate Cox regression were used to study the signature of ADRB1 + T cells for prognostic value. scRNA-seq data confirm the presence of exhausted markers in ADRB1 + T cells. The higher proportion in LUAD tumors as compared to LUSC was linked to more pronounced immune suppression and decreased T cell diversity. CellChat predicted extensive contacts between ADRB1 + T cells and macrophages, mainly through CCL and IFN-II signaling pathways. Inferred CNV evidenced evidence of malignant cells interacting with ADRB1 + T cells. In prognostic modeling based on ADRB1 + T cell signatures, high-risk populations were characterized by very poor overall survival, and ADRB1 was an independent prognostic factor in LUAD and LUSC. This paper describes ADRB1 for the first time as a novel immune checkpoint involved in T cell exhaustion in lung cancer. Indeed, ADRB1 + T cells are promising biomarker candidates; they may even become therapeutic targets in lung cancer. Indeed, proposing a pathway by which ADRB1 may be targeted, anti-tumor immunity may be boosted and better patient prognosis secured. Thus, functional studies and clinical trials will have to be done to test and discuss this proposed concept under a new heading in therapeutic strategy.