Targeting the PD-1/PD-L1 Axis for the Treatment of Non-Small-Cell Lung Cancer

Abstract

Lung cancer is the leading cause of cancer-specific death among Canadians, with non-small-cell lung cancer (nsclc) being the most common histologic variant. Despite advances in the understanding of the molecular biology of nsclc, the survival rate for this malignancy is still poor. It is now understood that, to evade detection and immune clearance, nsclc tumours overexpress the immunosuppressive checkpoint protein programmed death ligand 1 (PD-L1). Inhibiting the PD-1/PD-L1 axis with monoclonal antibodies has significantly changed the treatment landscape in nsclc during the last 5 years. Despite evidence of clinical response in some patients, only approximately 20% of patients obtain any durable benefit, and many of the patients who do respond ultimately relapse with drug-resistant disease. The identification of patients who are most likely to benefit from such therapy is therefore important. In the present review, we cover the basics of the PD-1/PD-L1 axis and its clinical significance in nsclc, biomarkers that are predictive of treatment response, relevant clinical trials of PD-1/PD-L1 blockade completed to date, and proposed mechanisms of acquired therapeutic resistance.

Insights Into Lung Cancer Immune-Based Biology, Prevention, and Treatment

“…This is supported by the fact that prolonged IFN-γ signaling in mouse models drives resistance to PD-1 blockade (64,65). PD-1's engagement with its ligand PD-L1, found on tumor cells, TIL, APC, endothelial, and epithelial cells, further dampens the apoptotic pathway, and induces anergy as well as T cell depletion (51,55,(66)(67)(68)(69). The expression of PD-L2, another ligand for PD-1, is limited to dendritic cells (DCs) and macrophages (51,67).…”

“…The expression of PD-L2, another ligand for PD-1, is limited to dendritic cells (DCs) and macrophages (51,67). Accumulating knowledge suggests that lung tumors overexpress the immunosuppressive protein, PD-L1, and inhibiting this pathway has led to durable benefit in a subset of advanced-stage NSCLC patients (69,70).…”

Integrative modeling of multi-omics data for predicting tumor mutation burden in lung cancer patients

“…Despite the improvements in chemotherapy and targeted therapy, the 5-year overall survival (OS) for patients with lung cancer remains poor [1,4]. Nevertheless, immunotherapy, especially the application of immune checkpoint inhibitors (ICIs), had made a great breakthrough in the treatment of cancer and dramatically increased survival rate and quality of life for patients with lung cancer [5][6][7][8][9].…”

Inhibition of COX-2 and EGFR by Melafolone Improves Anti-PD-1 Therapy through Vascular Normalization and PD-L1 Downregulation in Lung Cancer

“…Even after maximal safe resection and chemoradiation, the 5-year survival rate is dismal (Raju et al, 2018). Checkpoint blockade therapy, including monoclonal antibodies against programmed cell death 1 (PD-1) and its ligand (PD-L1), is a breakthrough for multiple types of cancer, including non-small cell lung cancer (NSCLC) (Meyers et al, 2018). Unfortunately, a significant subset of patients does not respond to immunotherapy and another subset eventually develops resistance after the initial response (O'Donnell et al, 2017).…”