Lung Cancer Immunotherapy: Beyond Common Immune Checkpoints Inhibitors

Abstract

Immunotherapy is an ever-expanding field in lung cancer treatment research. Over the past two decades, there has been significant progress in identifying immunotherapy targets and creating specific therapeutic agents, leading to a major paradigm shift in lung cancer treatment. However, despite the great success achieved with programmed death protein 1/ligand 1 (PD-1/PD-L1) monoclonal antibodies and with anti-PD-1/PD-L1 plus anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4), only a minority of lung cancer patients respond to treatment, and of these many subsequently experience disease progression. In addition, immune-related adverse events sometimes can be life-threatening, especially when anti-CTLA-4 and anti-PD-1 are used in combination. All of this prompted researchers to identify novel immune checkpoints targets to overcome these limitations. Lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin (Ig) and Immunoreceptor Tyrosine-Based Inhibitory Motif (ITIM) domain (TIGIT), T cell immunoglobulin and mucin-domain containing-3 (TIM-3) are promising molecules now under investigation. This review aims to outline the current role of immunotherapy in lung cancer and to examine efficacy and future applications of the new immune regulating molecules.

Keywords: emerging immune checkpoint inhibitors; immunotherapy; lung cancer; novel immune targets.

Figure 1

Timeline of Food and Drug Administration approval of immune checkpoints inhibitors in lung cancer. Image created with BioRender.com, accessed on 5 July 2022.

Figure 2

Expression of immune inhibitory checkpoints on different immune cells and tumor cells. Various immune checkpoints expressed by T cells and DC (a), B cells (b), B cells and NK (c), NK (d) and tumor cells. The figure shows the ligand for inhibitory receptors discussed in the review, the eventually co-stimulatory receptors activated by the ligands, and the contradictory or undefined roles of some of these molecules. Dendritic cells, (DC); natural killer, (NK); lymphocyte activation gene-3, (LAG-3); T cell immunoglobulin and mucin-domain containing-3, (TIM-3); T cell immunoreceptor with Ig and ITIM domains, (TIGIT); V-domain Ig suppressor of T cell activation, (VISTA); B7 homolog 3 protein, (B7H3); inducible T cell costimulatory, (ICOS; B and T cell lymphocyte attenuator (BTLA). Image created with BioRender.com. and accessed on 16 May 2022.