Checkpoint Proteins in Pediatric Brain and Extracranial Solid Tumors: Opportunities for Immunotherapy

Abstract

Pediatric brain and extracranial solid tumors are a diverse group of malignancies that represent almost half of all pediatric cancers. Standard therapy includes various combinations of surgery, cytotoxic chemotherapy, and radiation, which can be very harmful to a developing child, and survivors carry a substantial burden of long-term morbidities. Although these therapies have improved survival rates for children with solid tumors, outcomes still remain extremely poor for subsets of patients. Recently, immunosuppressive checkpoint molecules that negatively regulate immune cell function have been described. When found on malignant cells or in the tumor microenvironment, they contribute to immune evasion and tumor escape. Agents designed to inhibit these proteins have demonstrated significant efficacy in human adult solid tumor studies. However, there is limited research focusing on immune checkpoint molecules and inhibitors in pediatric solid tumors. In this review, we examine the current knowledge on immune checkpoint proteins with an emphasis on cytotoxic T lymphocyte antigen-4 (CTLA-4); programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1); OX-2 membrane glycoprotein (CD200); and indoleamine 2,3-dioxygenase (IDO). We review T-cell signaling, the mechanisms of action of these checkpoint molecules, pediatric preclinical studies on checkpoint proteins and checkpoint blockade, pediatric checkpoint inhibitor clinical trials conducted to date, and future immunotherapy opportunities for childhood cancers. Clin Cancer Res; 23(2); 342-50. ©2016 AACR.

Figure 1. Interaction of checkpoint proteins and receptors on tumor cells, antigen presenting cells (APCs), T cells and T regulatory cells

Programmed Death Ligand 1/2 (PD-L1/2), and CD200 are expressed on the tumor cell surface. Soluble CD200 (sCD200) exists in the serum of patients with solid tumors. Binding their ligands on T cells (PD-1, and CD200R, respectively) results in downregulation of the activated T cell immune response. Cytotoxic T lymphocyte Antigen-4 (CTLA-4) on the surface of Tregs and T cells can bind to B7-1/2 on APCs and interfere with T cell activation and proliferation via disruption of the B7-1/2-CD28 costimulatory complex. Indoleamine 2,3-dioxygenase (IDO), an enzyme found in the cytoplasm of tumor cells, catabolizes tryptophan into active metabolites, Kynurenic acid (KYNR), Quinolinic acid (QUIN), 3-Hydroxykynurenine (3-HK) and Picolinic acid (PIC), which contributes to T cell inhibition directly and indirectly through T regulatory cell (Treg) activation. Treg activation results in T cell inhibition through Treg cell surface CTLA-4 and PD-L1/2. The interaction between sCD200, tumor CD200 and Treg CD200R results in Treg activation and further T cell inhibition.

Figure 2. Maximizing the Antitumor Immune Response with Checkpoint Blockade

1) Activation of the immune response can occur through various approaches such as oncolytic viruses (oVirus) or vaccinations with tumor associated antigens (T_Ag) or other antigens such as tetanus toxoid. Antigen presenting cells (APC) process and present T_Ag to the T cell receptor (TCR) on T cells through major histocompatibility complex (MHC) I and II. 2) Various cytokines can be used to augment the antitumor immune response through stimulation of T cells, natural killer (NK) cells and/or macrophages. 3) Checkpoint protein inhibition enables continued activation of T cells to sustain the antitumor immune response and suppresses the development of immune tolerance to T_Ag mediated by T regulatory cells (Tregs).