PD-L1 Induction by Cancer-Associated Fibroblast-Derived Factors in Lung Adenocarcinoma Cells

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.

Time density curve of dynamic contrast‑enhanced computed tomography correlates with histological characteristics of pancreatic cancer

“…Cytokeratin AE1/AE3 is a pan-epithelial marker. Although there is no specific marker for CAFs, αSMA is widely used as a CAF marker in various human cancer types, such as lung cancer ( 18 ), cholangiocarcinoma ( 19 ), gastric cancer ( 20 ) and breast cancer ( 21 ). CD31 is a pan-vascular endothelial marker that is positive for both normal endothelial and tumor endothelial cells ( 22 ).…”

Clinical Implications of Exosomal PD-L1 in Cancer Immunotherapy

“…Current studies demonstrate that CAFs from a variety of tumor types release an array of factors that increase PD-L1 expression in tumor cells [ 84 , 85 ]. Evidence suggests that TGF- β 1, which is also found in CAF-derived exosomes, upregulates PD-L1 expression in a Smad2-dependent manner in NSCLC cells [ 86 , 87 ].…”

“…CAFs secrete CXCL2 and CXCL5 which induce PD-L1 expression in tumor cells via JAK/STAT and PI3K/AKT signaling, respectively [ 82 , 85 ]. These findings suggest that CAF-derived soluble factors upregulate PD-L1 expression in tumor cells by activating signaling pathways that have also been associated with exosomal PD-L1 release [ 84 , 88 , 89 ].…”

The Tumor Microenvironment in Liver Metastases from Colorectal Carcinoma in the Context of the Histologic Growth Patterns

“…Thus, cancer-associated fibroblasts can express PD-L1 [87][88][89][90] or may induce its expression in other cells [82][83][84], contributing to immunologic silencing. Particular CAF subtypes can also induce the expression of PD-1 and CTLA4 in surrounding lymphocytes [88][89][90][91], contributing to immunosuppression and resistance to immunotherapy. Liver endothelial sinusoidal cells can also induce T cell exhaustion and suppress innate responses [92].…”