MAPK pathway activity plays a key role in PD‐L1 expression of lung adenocarcinoma cells

Abstract

Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) have improved the survival of patients with non‐small cell lung cancer (NSCLC). Still, many patients do not respond to these inhibitors. PD‐L1 (CD274) expression, one of the factors that influences the efficacy of immune checkpoint inhibitors, is dynamic. Here, we studied the regulation of PD‐L1 expression in NSCLC without targetable genetic alterations in EGFR, ALK, BRAF, ROS1, MET, ERBB2 and RET. Analysis of RNA sequencing data from these NSCLCs revealed that inferred IFNγ, EGFR and MAPK signaling correlated with CD274 gene expression in lung adenocarcinoma. In a representative lung adenocarcinoma cell line panel, stimulation with EGF or IFNγ increased CD274 mRNA and PD‐L1 protein and membrane levels, which were further enhanced by combining EGF and IFNγ. Similarly, tumor cell PD‐L1 membrane levels increased after coculture with activated peripheral blood mononuclear cells. Inhibition of the MAPK pathway, using EGFR inhibitors cetuximab and erlotinib or the MEK 1 and 2 inhibitor selumetinib, prevented EGF‐ and IFNγ‐induced CD274 mRNA and PD‐L1 protein and membrane upregulation, but had no effect on IFNγ‐induced MHC‐I upregulation. Interestingly, although IFNγ increases transcriptional activity of CD274, MAPK signaling also increased stabilization of CD274 mRNA. In conclusion, MAPK pathway activity plays a key role in EGF‐ and IFNγ‐induced PD‐L1 expression in lung adenocarcinoma without targetable genetic alterations and may present a target to improve the efficacy of immunotherapy. © 2019 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Anti-EGFR Fibronectin Bispecific Chemically Self-Assembling Nanorings (CSANs) Induce Potent T cell Mediated Anti-Tumor Response and Downregulation of EGFR Signaling and PD-1/PD-L1 Expression

“…While current EGFR therapies have shown efficacy against certain TNBC cells, they are ineffective against the MDA-MB-231 cells used in this study, due to the presence of the G13D KRAS mutation (33). Consistent with these observations, suppression of EGFR signaling by TKIs and targeted monoclonal antibodies has been shown to suppress tumor expression of PD-L1 (45). These observations were not described for alternative protein scaffolds, EGFR CAR-T cells or EGFR bispecific T cell engagers (45).…”

“…Consistent with these observations, suppression of EGFR signaling by TKIs and targeted monoclonal antibodies has been shown to suppress tumor expression of PD-L1 (45). These observations were not described for alternative protein scaffolds, EGFR CAR-T cells or EGFR bispecific T cell engagers (45). Thus, treatment with EGFR/CD3-CSANs resulted in not only T cell proliferation and directed cell killing, but a reduction in the immunosuppressive tumor microenvironment.…”

Basis of PD1/PD-L1 Therapies

“…Thus, PD-L1 expression can be induced by EGF signaling and enhanced by activating mutations in the EGF-R gene and contributes to the EGF-R-driven immune escape [85]. In addition, the Ras/Raf/MEK/MAPK-ERK pathway was also linked to PD-L1 overexpression in various cancers, while respective inhibitors lead to a downregulation of PD-L1 expression [86,87]. PD-L1 expression could be upregulated by cell contact.…”

Mitogen-Activated Protein Kinase Inhibitors and T-Cell-Dependent Immunotherapy in Cancer

“…Early results suggest that this combined approach induces robust antitumor effects mediated predominantly by cytotoxic T lymphocytes [19]. Additionally, Selumetinib also appears to attenuate PD-L1 expression without impeding interferon gamma (IFNγ)-induced MHC-I upregulation in nonsmall cell lung cancer cells, suggesting that it may also benefit patients receiving cancer immunotherapy [39]. The MEK inhibitor G-38963, along with anti-PD-L1 therapy promotes effector function and lifespan of tumor-infiltrating CD8 + T-cells leading to synergistic inhibition in tumor growth [40].…”