Abstract

The last several years have seen the introduction into clinical medicine of a family of reagents directed towards so-called “checkpoint inhibitors”, which act at gateways in a developing immune response to regulate unwanted and/or harmful selfdirected activation responses. The molecules involved at such gateways generally belong to an extended immunoglobulin supergene family, and contribute inhibitory signals to dampen over-exuberant responses. They include, but are not limited to, molecules of the CD28/cytotoxic T-lymphocyte antigen-4 (CTLA-4):B7.1/B7.2 receptor/ligand family; PD-1 and PDL-1; CD200 and CD200R; TIGIT and VISTA and their respective ligands (VSIG-3/IGSF11, Nectin), all of which are presumed to play a physiological role in maintaining natural self-tolerance. In the field of cancer immunotherapy, where the ultimate clinical goal is to improve immuno-targeting of cancer cells, triggering these checkpoint inhibitory signaling pathways, has the potential to thwart effective tumor immunity. This in turn has led to the characterization and application of multiple reagents, including antibodies and other designed inhibitory molecules, which can act as checkpoint blockade agents. Such reagents have had a dramatic effect on human cancer treatment, with marked success for anti-CTLA-4 and PD-1 in particular in clinical trials. This review elaborates on the promise on other more under-appreciated target molecules for checkpoint blockade in human B cell malignancies and solid tumors, particularly CD200:CD200R, and describes both the background, and newer studies, which highlight the potential importance of targeting the CD200:CD200R dyad in cancer immunobiology/therapy. 

Keywords: Checkpoint blockade; Immunotherapy; Oncology; Inhibitory pathways; Stimulatory pathways; Activated T cells

Introduction

T cell activated immune responses to both nominal antigen and tumor-expressed antigens follows T cell receptor engagement of antigen expressed on suitable antigen-presenting-cells and delivery of suitable co-stimulatory signals (generally via the CD28: CD80/CD86 axis), along with an activation signal to antigen-presenting cells [1]. Early studies directed at improving cancer immunotherapy were directed towards enhancing antigen presentation, and/or co-stimulatory signals for cancer therapy [2,3]. However, it has become clear over the past 10-20 years that immunity is also regulated by the expression and engagement of inhibitory molecules and their receptors in the immune system [47], and activation of such inhibitory ligand: receptors leads to socalled checkpoint blockade [8-10]. In turn, reversal of checkpoint blockade can release activation of anti-tumor responses [11-13]. 

The discussion that follows highlights some of the more recent data exploring checkpoint blockade in cancer care with the most common molecules currently explored in both model systems and in clinical situations [12,13] (a summary of checkpoint blockade studies is included in Table 1, and a schematic for the action of many reagents targeting key checkpoints in tumor therapy in Figure 1). A major emphasis of this review however, as will be apparent later, is to focus on the growing body of evidence to support the notion that targeting a novel ligand:receptor dyad which my laboratory has explored at length, CD200:CD200R, is an important, and to date overlooked, area with great therapeutic potential in both solid tumors and B cell malignancies [14].

Footnotes to Table:

1. Co-stimulatory/inhibitor pathway targeted for manipulation
2. Reagents used to target interaction under investigation
3. Situation in which reagents are used; E=experimental model system; C=clinical scenario
4. TEM=tumor microenvironment; CAR-T=genetically engineered chimeric antigen-receptor T cells

Table 1: Summary of checkpoint blockade, alone or in combination, in tumor Immunotherapy.