Immune Checkpoint Inhibitors for Lung Cancer Treatment: A Review

Abstract

The treatment of lung cancer has changed drastically in recent years owing to the advent of immune checkpoint inhibitors (ICIs). A 1992 study reported that programmed cell death-1 (PD-1), an immune checkpoint molecule, is upregulated during the induction of T cell death. Since then, various immunoregulatory mechanisms involving PD-1 have been clarified, and the successful use of PD-1 blockers in anticancer therapy eventually led to the development of the current generation of ICIs. Nivolumab was the first ICI approved for treating lung cancer in 2014. Since then, various ICIs such as pembrolizumab, atezolizumab, and durvalumab have been successively introduced into clinical medicine and have shown remarkable efficacy. The introduction of ICIs constituted a major advancement in lung cancer treatment, but disease prognosis continues to remain low. Therefore, new molecular-targeted therapies coupled with existing anticancer drugs and radiotherapy have recently been explored. This review encompasses the current status, challenges, and future perspectives of ICI treatment in lung cancer.

Keywords: PD-1; biomarker; immune checkpoint inhibitors; non-small-cell lung cancer.

Figure 1

Immune checkpoint inhibitors in cancer treatment. Notes: Inability to activate T cells in the tumor microenvironment through the suppressive effect of Tregs or through immune checkpoints allows cancer cells to escape immune attack, survive, and grow. B7 ligands expressed on antigen-presenting cells bind to TCR and induce T cell amplification and immune response. Alternatively, binding of B7 ligands to CTLA-4 expressed on T cells suppresses their activity. CTLA-4 also enhances the activity of Tregs leading to immunosuppressive activity. PD-1 is expressed on activated T cells. PD-1 binds to its PD-L1 leading to the anergy of T cells, further promoting inhibitory signals. Pharmacological inhibition of immune checkpoints with monoclonal antibodies restores T cell antitumor activity and relieves immunosuppression. Abbreviations: CTLA-4: cytotoxic T-lymphocyte antigen 4; MHC: major histocompatibility complex; PD-1: programmed cell death-1; PD-L1: programmed cell death-1 ligand; TCR: T cell receptor; Tregs: regulatory T cells; APC: antigen presenting cell.