Tumor-Derived Vaccines Containing CD200 Inhibit Immune Activation: Implications for Immunotherapy

Abstract

There are over 400 ongoing clinical trials using tumor-derived vaccines. This approach is especially attractive for many types of brain tumors, including glioblastoma, yet so far the clinical response is highly variable. One contributor to poor response is CD200, which acts as a checkpoint blockade, inducing immune tolerance. We demonstrate that, in response to vaccination, glioma-derived CD200 suppresses the anti-tumor immune response. In contrast, a CD200 peptide inhibitor that activates antigen-presenting cells overcomes immune tolerance. The addition of the CD200 inhibitor significantly increased leukocyte infiltration into the vaccine site, cytokine and chemokine production, and cytolytic activity. Our data therefore suggest that CD200 suppresses the immune system's response to vaccines, and that blocking CD200 could improve the efficacy of cancer immunotherapy.

CD200 immune checkpoint reversal at the site of tumor vaccine inoculation: A novel approach to glioblastoma immunotherapy

“…6,7,8,9 The CD200 immune checkpoint results in suppression of the secretion of proinflammatory cytokines, including IL2 and IFNg, 10,11 and increases production of myeloid derived suppressor cells (MDSCs) 12 and T regulatory cells (Tregs), 12,13,14 resulting in compromised anti-tumor activity. Previously, we revealed the following mechanisms employed by the CD200 protein: (1) it is upregulated in GBM-associated endothelial cells, creating an immunological barrier around the tumor microenvironment; 10 and (2) it is shed from tumors 12,15 and interacts with the inhibitory CD200 receptor (CD200R1) on immune cells in the tumor microenvironment and within the draining lymph nodes. 10,15 Our research focuses on the development of a therapeutic agent that targets the CD200 immune checkpoint regulatory system, which modulates the immune response through CD200R1.…”

“…Previously, we revealed the following mechanisms employed by the CD200 protein: (1) it is upregulated in GBM-associated endothelial cells, creating an immunological barrier around the tumor microenvironment; 10 and (2) it is shed from tumors 12,15 and interacts with the inhibitory CD200 receptor (CD200R1) on immune cells in the tumor microenvironment and within the draining lymph nodes. 10,15 Our research focuses on the development of a therapeutic agent that targets the CD200 immune checkpoint regulatory system, which modulates the immune response through CD200R1. 10,12 In addition to the inhibitory CD200R1, there are a series of activation receptors (CD200AR2, 3, 4 & 5) in mice.…”

“…10,15 Our research focuses on the development of a therapeutic agent that targets the CD200 immune checkpoint regulatory system, which modulates the immune response through CD200R1. 10,12 In addition to the inhibitory CD200R1, there are a series of activation receptors (CD200AR2, 3, 4 & 5) in mice. 16 We developed a peptide-based strategy to engage these activation receptors on immune cells 10 and demonstrated that the inhibitory effects of CD200 protein can be surmounted by selectively engaging CD200ARs 17,11 , using specific synthetic peptide ligands (CD200AR-L) that we identified through protein sequencing and structural analyses of CD200.…”

“…10,12 In addition to the inhibitory CD200R1, there are a series of activation receptors (CD200AR2, 3, 4 & 5) in mice. 16 We developed a peptide-based strategy to engage these activation receptors on immune cells 10 and demonstrated that the inhibitory effects of CD200 protein can be surmounted by selectively engaging CD200ARs 17,11 , using specific synthetic peptide ligands (CD200AR-L) that we identified through protein sequencing and structural analyses of CD200. 10 The ability to overpower the suppressive effects of CD200 is lost when using a scrambled CD200AR-L or CD200ARKO mice, demonstrating that these peptides mimic active sites within the CD200 protein to modulate CD200AR activity and result in immune stimulation.…”

“…16 We developed a peptide-based strategy to engage these activation receptors on immune cells 10 and demonstrated that the inhibitory effects of CD200 protein can be surmounted by selectively engaging CD200ARs 17,11 , using specific synthetic peptide ligands (CD200AR-L) that we identified through protein sequencing and structural analyses of CD200. 10 The ability to overpower the suppressive effects of CD200 is lost when using a scrambled CD200AR-L or CD200ARKO mice, demonstrating that these peptides mimic active sites within the CD200 protein to modulate CD200AR activity and result in immune stimulation. 10,12 We also tested the efficacy of the CD200AR-L in companion dog spontaneous high-grade glioma using a canine-specific CD200AR-L. 18 In this study, subcutaneous injection of the canine CD200AR-L prior to and during administration of autologous tumor lysate vaccine significantly enhanced the efficacy of the vaccine, doubling the median overall survival time compared to dogs receiving tumor lysates alone.…”