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.

Keywords: Lung cancer; PD-1/PD-L1; immune checkpoints; immunotherapy; nsclc.

FIGURE 1

A possible mechanism for acquired resistance to PD-1 inhibition. Anagnostou and colleagues discovered that acquired resistance to blockade of the PD-1/PD-L1 axis can potentially be explained by a shifting mutational landscape, which might cause the loss of neoantigens. That loss abrogates the ability of T cells in the tumour microenvironment to recognize the malignant cells as foreign, which renders therapy with PD-1 axis blockade ineffective. CD8+ T cells, regulatory T cells (T regs) and myeloid-derived suppressor cells (MDSCs) are all pictured here as part of the tumour microenvironment. ICI = immune checkpoint inhibitor; TCR = T cell receptor; MHC = major histocompatibility complex.