Abstract
BackgroundMalignant transformation and progression of cancer are driven by the co-evolution of cancer cells and their dysregulated tumor microenvironment (TME). Recent studies on immunotherapy demonstrate the efficacy in reverting the anti-tumoral function of T cells, highlighting the therapeutic potential in targeting certain cell types in TME. However, the functions of other immune cell types remain largely unexplored.ResultsWe conduct a single-cell RNA-seq analysis of cells isolated from tumor tissue samples of non-small cell lung cancer (NSCLC) patients, and identify subtypes of tumor-infiltrated B cells and their diverse functions in the progression of NSCLC. Flow cytometry and immunohistochemistry experiments on two independent cohorts confirm the co-existence of the two major subtypes of B cells, namely the naïve-like and plasma-like B cells. The naïve-like B cells are decreased in advanced NSCLC, and their lower level is associated with poor prognosis. Co-culture of isolated naïve-like B cells from NSCLC patients with two lung cancer cell lines demonstrate that the naïve-like B cells suppress the growth of lung cancer cells by secreting four factors negatively regulating the cell growth. We also demonstrate that the plasma-like B cells inhibit cancer cell growth in the early stage of NSCLC, but promote cell growth in the advanced stage of NSCLC. The roles of the plasma-like B cell produced immunoglobulins, and their interacting proteins in the progression of NSCLC are further validated by proteomics data.ConclusionOur analysis reveals versatile functions of tumor-infiltrating B cells and their potential clinical implications in NSCLC.
Highlights
Non-small cell lung cancer (NSCLC) is the leading life-threatening cancer in the world [1, 2]
We merged the single-cell transcriptomic profiles collected from different samples for a uniform manifold approximation and projection (UMAP)-based cell clustering analysis, the cell types of which were further annotated by using known cell type-specific gene markers [27]
The C0 and C11 cluster of T cells are with high expression level of CD3E, CD8A, and CD8B, suggesting CD8+ T cells; the C13 cluster of T cells expressed high level of NCAM1 (CD56), CD3E, and NKG7 and low level of CD8A and CD8B, suggesting possible natural killer T (NKT) cells; the C1 cluster expressed CD3E and CD69 genes, indicating CD69+ T cells; the C21 expressed high levels of CD4 and GZMB, indicating CD4+ CTLs; the C3 cluster is with high expression of FOXP3 and IL2RA (CD25), which are possible Tregs
Summary
Non-small cell lung cancer (NSCLC) is the leading life-threatening cancer in the world [1, 2]. Chen et al Genome Biology (2020) 21:152 microenvironment (TME), the variations in which were manifested by different abundance and functions of tumor-infiltrating lymphocytes (TIL), myeloid, and other stromal cells. While T cells have been widely studied and therapeutically targeted in immunotherapy, currently approved immune checkpoint inhibitors only achieved 20–25% response rate in unscreened NSCLC [4,5,6,7,8]. A comprehensive characterization of the NSCLC immuno-landscape including the distribution and role of immune cell subtypes, especially B lymphocytes, is necessary for understanding the non-responsiveness mechanisms and discovering novel biomarkers and therapeutic strategies. Recent studies on immunotherapy demonstrate the efficacy in reverting the anti-tumoral function of T cells, highlighting the therapeutic potential in targeting certain cell types in TME. The functions of other immune cell types remain largely unexplored
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