Therapeutic targeting of immune checkpoints with small molecule inhibitors

Abstract

Immune checkpoints are known to contribute to tumor progression by enhancing cancer's ability to evade the immune system and metastasize. Immunotherapies, including monoclonal antibodies, have been developed to target specific immunosuppressive molecules on the membranes of cancer cells and have proven revolutionary in the field of oncology. Recently, small molecule inhibitors (SMIs) have gained increased attention in cancer research with potential applications in immunotherapy. SMIs have desirable benefits over large-molecule inhibitors, such as monoclonal antibodies, including greater cell permeability, organ specificity, longer half-lives, cheaper production costs, and the possibility for oral administration. This paper will review the mechanisms by which noteworthy and novel immune checkpoints contribute to tumor progression, and how they may be targeted by SMIs and epigenetic modifiers to offer possible adjuvants to established therapeutic regimens. SMIs target immune checkpoints in several ways, such as blocking signaling between tumorigenic factors, building immune tolerance, and direct inhibition via epigenetic repression of immune inhibitory molecules. Further investigation into combination therapies utilizing SMIs and conventional cancer therapies will uncover new treatment options that may provide better patient outcomes across a range of cancers.

Keywords: Small molecule inhibitors; cancer progression; epigenetics; immune checkpoints; tumor microenvironment.

Figure 1

A graphic representation of the potential benefits that SMIs (including epigenetic inhibitors) may yield in addition to conventional therapies or immunotherapies. Upregulation of tumor suppressors may cause cell cycle arrest and halting of various oncogenic properties such as angiogenesis, immune evasion, and metastasis. SMIs directed towards immune checkpoints such as PD-1/PD-L1, CTLA-4, LAG-3, OX40, TIM-3, and B7-H3 may also produce this same effect. Additionally, SMIs can target epigenetic proteins such as EZH2 to inhibit the methylation of specific histones towards specific states such as H3K9me3, H3K27me3, and H3K4ac. Inhibition of these pathways result in cell cycle arrest and inhibition of angiogenesis, immune evasion, and metastasis.