Abstract
Cancer-associated fibroblasts (CAFs) exert various effects upon biological behaviours of cancer. In this study, we examined the correlation of CAFs with the intra-tumoural immune system in the lung adenocarcinoma microenvironment. We studied 27 and 113 cases of lung adenocarcinoma tentatively as Cohorts 1 and 2, respectively. The patients in Cohort 1 received epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) for recurrent lung adenocarcinoma. α-smooth muscle actin (α-SMA), a surrogate marker for CAFs, was examined by immunohistochemistry. We then examined the effects of CAFs isolated from lung cancer tissues on programmed death ligand 1 (PD-L1) expression in lung adenocarcinoma cell lines. No significant associations were detected between α-SMA status and the ratios of CD8/CD4 and Foxp3/CD8 in Cohort 1. However, α-SMA status was significantly associated with PD-L1 status in both Cohorts 1 and 2. Conditioned medium of CAFs significantly induced PD-L1 expression in lung adenocarcinoma cell lines, A549, PC-9, and H1975. Among the cytokines examined by antibody array, C-X-C motif chemokine ligand 2 (CXCL2) increased PD-L1 mRNA expression in these cell lines. CXCL2 is therefore considered to have a potential to induce PD-L1 expression in lung adenocarcinoma cells as a result of an interaction between carcinoma cells and CAFs. These findings did firstly demonstrate that CAFs indirectly influenced tumour immunity through increasing PD-L1 expression in lung adenocarcinoma cells.
Highlights
Lung adenocarcinoma cells have been well known to interact with various compartments of tissue microenvironment in cancer tissue, including immune cells, microvessels, and fibroblasts.Activated fibroblasts within cancer stroma are termed cancer-associated fibroblasts (CAFs) and have been known to be associated with cancer growth, invasion, migration, metastasis, and therapeutic resistance through secretion of various soluble factors, including cytokines, chemokines, growthCancers 2019, 11, 1257; doi:10.3390/cancers11091257 www.mdpi.com/journal/cancersCancers 2019, 11, 1257 factors, and exosomes [1,2,3,4,5,6]
We evaluated the correlation between immunoreactivity of α-smooth muscle actin (α-SMA), a well-known marker of CAFs, and subpopulations of tumour-infiltrating lymphocytes determined by CD3, CD4, CD8, and Foxp3, in 27 lung adenocarcinoma tissues
We examined the effects of IL-8 and OPG on PD ligand 1 (PD-L1) expression in lung adenocarcinoma cell lines
Summary
Lung adenocarcinoma cells have been well known to interact with various compartments of tissue microenvironment in cancer tissue, including immune cells, microvessels, and fibroblasts. Activated fibroblasts within cancer stroma are termed cancer-associated fibroblasts (CAFs) and have been known to be associated with cancer growth, invasion, migration, metastasis, and therapeutic resistance through secretion of various soluble factors, including cytokines, chemokines, growth. CAFs secrete inflammatory cytokines and growth factors, which subsequently activate oncogenic pathways in carcinoma cells. We first examined the influence of CAFs on PD-L1 expression in carcinoma cells in lung adenocarcinoma tissue. We evaluated the correlation between immunoreactivity of α-smooth muscle actin (α-SMA), a well-known marker of CAFs, and subpopulations of tumour-infiltrating lymphocytes determined by CD3, CD4, CD8, and Foxp, in 27 lung adenocarcinoma tissues. Cytokines released from CAFs were detected using a cytokine array, and the effects of cytokines on PD-L1 expression in lung adenocarcinoma cell lines were studied
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