Tumor‐associated macrophages (TAMs)‐derived osteopontin (OPN) upregulates PD‐L1 expression and predicts poor prognosis in non‐small cell lung cancer (NSCLC)

Abstract

Background Programmed cell death ligand 1 (PD‐L1) is widely known as an immune checkpoint molecule in tumor cells. Osteopontin (OPN) is expressed by both tumor cells and tumor‐associated macrophages (TAMs), and both autocrine and paracrine of OPN are considered to be involved in tumor metastasis, proliferation and immunosuppression. However, little is known about the relationship between OPN expressed in TAMs (TOPN) and PD‐L1 in non‐small cell lung cancer (NSCLC). Methods Tissue microarray was used to detect the expression of TOPN, TAMs and PD‐L1 by multiple quantitative fluorescence staining in 509 NSCLC patients undergoing complete pulmonary resection. The correlations between TOPN, PD‐L1 and clinicopathological data were analyzed. An in vitro coculture system was established to investigate the crosstalk between TOPN and neoplastic PD‐L1. In vivo, the intrinsic features of PD‐L1 in NSCLC xenografts were evaluated after being coinjected with OPN‐positive TAMs, and a series of key cytokines and chemokines were detected in the tumor microenvironment. Results A positive association between the TOPN and PD‐L1 expression in tumor tissues from 509 patients with NSCLC was verified. In addition, TOPN and PD‐L1 were independent prognostic factors for overall survival (OS) and disease‐free survival (DFS) of NSCLC patients. Moreover, TOPN upregulated PD‐L1 expression in NSCLC cells through the nuclear factor‐κB (NF‐κB) pathway in vitro TOPN induced the PD‐L1 expression promoted the tumor growth in tumor‐bearing mice, altering immune‐related cytokines and chemokines. Conclusions TOPN regulates PD‐L1 expression through the NF‐κB pathway in NSCLS, which is a potential independent biomarker and target for prognosis as well as immunotherapy.

Roles of tumor-associated macrophages in anti-PD-1/PD-L1 immunotherapy for solid cancers

“…Osteopontin (OPN) is expressed in both tumor cells and TAMs. OPN-expressing macrophages upregulate PD-L1 expression via regulating the NF-kB/p65 pathway and aggravate tumor progression [ 127 ]. Interleukins of TAMs, such as IL-1a, IL-10, IL-27, IL-6, etc., also significantly influence the expression of PD-L1.…”

Osteopontin, a Key Multifaceted Regulator in Tumor Progression and Immunomodulation

“…PD-L1 is one such immune checkpoint molecule on tumor cells which binds with its receptor, PD-1 on T cells and induces T cell dysfunction. It has been demonstrated that TAM derived OPN increased the expression of PD-L1 in NSCLC via NF-κB signalling resulting in suppression of anti-tumor immune response [144]. In another reports, PD-L1 expression was upregulated on HCC by OPN through induction of CSF1-CSF1R pathway in macrophages [145].…”

Differential gene expression analysis pipelines and bioinformatic tools for the identification of specific biomarkers: A review

“…Once differentially expressed genes have been identified and their potential implications understood, it is then crucial to present these data in a clear and intuitive graphic format. Visualization allows researchers to easily observe trends, patterns, and anomalies in the data [43] , [44] , [45] , [46] .…”