Emerging therapeutic strategies for enhancing sensitivity and countering resistance to programmed cell death protein 1 or programmed death-ligand 1 inhibitors in non-small cell lung cancer

Abstract

The availability of agents targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint has transformed treatment of advanced and/or metastatic non-small cell lung cancer (NSCLC). However, a substantial proportion of patients treated with these agents do not respond or experience only a brief period of clinical benefit. Even among those whose disease responds, many subsequently experience disease progression. Consequently, novel approaches are needed that enhance antitumor immunity and counter resistance to PD-(L)1 inhibitors, thereby improving and/or prolonging responses and patient outcomes, in both PD-(L)1 inhibitor-sensitive and inhibitor-resistant NSCLC. Mechanisms contributing to sensitivity and/or resistance to PD-(L)1 inhibitors in NSCLC include upregulation of other immune checkpoints and/or the presence of an immunosuppressive tumor microenvironment, which represent potential targets for new therapies. This review explores novel therapeutic regimens under investigation for enhancing responses to PD-(L)1 inhibitors and countering resistance, and summarizes the latest clinical evidence in NSCLC.

Keywords: drug resistance; immunotherapy; neoplasm; non-small cell lung cancer; programmed cell death protein 1; programmed death-ligand 1; tumor escape.

FIGURE 1

Potential pathways contributing to sensitivity and resistance to PD-(L)1 inhibitors in NSCLC, and selected drug targets. APC, antigen-presenting cell; CEACAM-1, carcinoembryonic antigen-related cell adhesion molecule 1; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; DC, dendritic cell; HMGB1, high-mobility group protein B1; IFN, interferon; IL, interleukin; IL-R, interleukin receptor; LAG-3, lymphocyte-activation gene-3; mAb, monoclonal antibody; MHC II, major histocompatibility complex class II; NK, natural killer; NSCLC, non–small cell lung cancer; PD-(L)1, programmed cell death protein 1 or programmed death-ligand 1; PtdSer, phosphatidylserine; STING, stimulator of interferon genes; TGF-βR, transforming growth factor β receptor; TCR, T-cell receptor; TGF, transforming growth factor; TIGIT, T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains; TIM-3, T-cell immunoglobulin- and mucin-domain-containing molecule 3; TK, tyrosine kinase; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.