PD-L1 Overexpression With Activating EGFR Mutations in NSCLC
PD-L1 Overexpression With Activating EGFR Mutations in NSCLC
Background Recent clinical trials have shown that immune-checkpoint blockade yields a clinical response in a subset of individuals with advanced nonsmall-cell lung cancer (NSCLC). We examined whether the expression of programmed death–ligand 1 (PD-L1) is related to clinicopathologic or prognostic factors in patients with surgically resected NSCLC.
Patients and methods The expression of PD-L1 was evaluated by immunohistochemical analysis in 164 specimens of surgically resected NSCLC. Cell surface expression of PD-L1 in NSCLC cell lines was quantified by flow cytometry.
Results Expression of PD-L1 in tumor specimens was significantly higher for women than for men, for never smokers than for smokers, and for patients with adenocarcinoma than for those with squamous cell carcinoma. Multivariate analysis revealed that the presence of epidermal growth factor receptor gene (EGFR) mutations and adenocarcinoma histology were significantly associated with increased PD-L1 expression in a manner independent of other factors. Cell surface expression of PD-L1 was also significantly higher in NSCLC cell lines positive for activating EGFR mutations than in those with wild-type EGFR. The EGFR inhibitor erlotinib downregulated PD-L1 expression in the former cell lines but not in the latter, suggesting that PD-L1 expression is increased by EGFR signaling conferred by activating EGFR mutations. A high level of PD-L1 expression in resected tumor tissue was associated with a significantly shorter overall survival for NSCLC patients.
Conclusions High expression of PD-L1 was associated with the presence of EGFR mutations in surgically resected NSCLC and was an independent negative prognostic factor for this disease.
Lung cancer is the leading cause of cancer death worldwide. Recent advances in targeted therapy, however, have led to a major paradigm shift in clinical oncology. Molecularly targeted drugs such as erlotinib and crizotinib have thus greatly improved the clinical course for nonsmall-cell lung cancer (NSCLC) patients with sensitizing epidermal growth factor receptor (EGFR) gene mutations or anaplastic lymphoma kinase (ALK) gene translocations, respectively. Despite these advances, however, the prognosis of individuals with NSCLC who do not harbor an identifiable driver oncogene remains poor.
Blockade of immune checkpoints with monoclonal antibodies has also recently emerged as a new therapeutic tool in oncology. Programmed death 1 (PD1), which belongs to the CD28 family of proteins, is a receptor expressed on the surface of T cells that regulates their activation and proliferation. Its ligand, programmed death–ligand 1 (PD-L1), is frequently overexpressed in many types of human cancer. The binding of PD-L1 to PD1 induces apoptosis or exhaustion in activated T cells, and blockade of this interaction has been shown to enhance the antitumor activity of T cells. Recent clinical trials found that inhibition of the PD-L1–PD1 interaction with antibodies specific for these proteins had promising antitumor efficacy in patients with various malignancies including NSCLC. The clinical relevance of PD-L1 expression in NSCLC has remained unclear, however. We have therefore now examined PD-L1 expression in surgically resected NSCLC specimens and analyzed its associated clinicopathologic characteristics and prognostic relevance.
Abstract and Introduction
Abstract
Background Recent clinical trials have shown that immune-checkpoint blockade yields a clinical response in a subset of individuals with advanced nonsmall-cell lung cancer (NSCLC). We examined whether the expression of programmed death–ligand 1 (PD-L1) is related to clinicopathologic or prognostic factors in patients with surgically resected NSCLC.
Patients and methods The expression of PD-L1 was evaluated by immunohistochemical analysis in 164 specimens of surgically resected NSCLC. Cell surface expression of PD-L1 in NSCLC cell lines was quantified by flow cytometry.
Results Expression of PD-L1 in tumor specimens was significantly higher for women than for men, for never smokers than for smokers, and for patients with adenocarcinoma than for those with squamous cell carcinoma. Multivariate analysis revealed that the presence of epidermal growth factor receptor gene (EGFR) mutations and adenocarcinoma histology were significantly associated with increased PD-L1 expression in a manner independent of other factors. Cell surface expression of PD-L1 was also significantly higher in NSCLC cell lines positive for activating EGFR mutations than in those with wild-type EGFR. The EGFR inhibitor erlotinib downregulated PD-L1 expression in the former cell lines but not in the latter, suggesting that PD-L1 expression is increased by EGFR signaling conferred by activating EGFR mutations. A high level of PD-L1 expression in resected tumor tissue was associated with a significantly shorter overall survival for NSCLC patients.
Conclusions High expression of PD-L1 was associated with the presence of EGFR mutations in surgically resected NSCLC and was an independent negative prognostic factor for this disease.
Introduction
Lung cancer is the leading cause of cancer death worldwide. Recent advances in targeted therapy, however, have led to a major paradigm shift in clinical oncology. Molecularly targeted drugs such as erlotinib and crizotinib have thus greatly improved the clinical course for nonsmall-cell lung cancer (NSCLC) patients with sensitizing epidermal growth factor receptor (EGFR) gene mutations or anaplastic lymphoma kinase (ALK) gene translocations, respectively. Despite these advances, however, the prognosis of individuals with NSCLC who do not harbor an identifiable driver oncogene remains poor.
Blockade of immune checkpoints with monoclonal antibodies has also recently emerged as a new therapeutic tool in oncology. Programmed death 1 (PD1), which belongs to the CD28 family of proteins, is a receptor expressed on the surface of T cells that regulates their activation and proliferation. Its ligand, programmed death–ligand 1 (PD-L1), is frequently overexpressed in many types of human cancer. The binding of PD-L1 to PD1 induces apoptosis or exhaustion in activated T cells, and blockade of this interaction has been shown to enhance the antitumor activity of T cells. Recent clinical trials found that inhibition of the PD-L1–PD1 interaction with antibodies specific for these proteins had promising antitumor efficacy in patients with various malignancies including NSCLC. The clinical relevance of PD-L1 expression in NSCLC has remained unclear, however. We have therefore now examined PD-L1 expression in surgically resected NSCLC specimens and analyzed its associated clinicopathologic characteristics and prognostic relevance.
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