Newly Emerging Immune Checkpoints: Promises for Future Cancer Therapy.

Robert Torphy,Yuwen Zhu,Richard Schulick

doi:10.3390/ijms18122642

Abstract

Cancer immunotherapy has been a great breakthrough, with immune checkpoint inhibitors leading the way. Despite the clinical effectiveness of certain immune checkpoint inhibitors, the overall response rate remains low, and the effectiveness of immunotherapies for many tumors has been disappointing. There is substantial interest in looking for additional immune checkpoint molecules that may act as therapeutic targets for cancer. Recent advances during the last decade have identified several novel immune checkpoint targets, including lymphocyte activation gene-3 (LAG-3), B and T lymphocyte attenuator (BTLA), programmed death-1 homolog (PD-1H), T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIM-3)/carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), and the poliovirus receptor (PVR)-like receptors. The investigations into these molecules have generated promising results in preclinical studies. Herein, we will summarize our current progress and understanding of these newly-characterized immune checkpoints and their potential application in cancer immunotherapy.

Highlights

Targeting cosignaling molecules for cancer immunotherapy is a rapidly expanding area in oncology research
Key to the understanding of cosignaling molecules is that recognition of an antigen by a T cell is insufficient for T cell activation
This concept was first demonstrated through the costimulatory receptor CD28, which binds to the ligands B7-1 (CD80) and B7-2 (CD86) on antigen-presenting cells (APCs), allowing for T cell activation [2,3]

Summary

Introduction

Targeting cosignaling molecules for cancer immunotherapy is a rapidly expanding area in oncology research. Breakthroughs have subsequently been made in clinical cancer immunotherapy by targeting checkpoints CTLA-4, and especially programmed cell death protein 1 (PD-1), which has resulted in United States Food and Drug Administration (FDA) approval for anti-CTLA-4 and anti-PD-1 therapies. One promising attribute of PD-1 in cancer immunotherapy is that the expression of PD-1 ligands, especially PD-L1, has been shown to be upregulated in a variety of tumors, and blockade of PD-L1 signal can sensitize tumors to cytotoxic T lymphocyte (CTL) killing [25] These data suggest that anti-PD-1 treatments may be more specific in targeting cancer cells, resulting in less systemic toxicity. Durvalumab and avelumab are the other two anti-PD-L1 mAbs approved for patients with locally advanced or metastatic urothelial carcinoma that fails platinum-containing chemotherapy [44] All these drugs targeting PD-L1 are under active clinical trials for multiple solid cancer types

Newly Emerging Immune Checkpoints

Future Outlook