Immune Checkpoint Blockade Biology in Mouse Models of Glioblastoma

Abstract

Glioblastoma Multiforme (GBM) is a highly malignant primary brain cancer that is associated with abysmal prognosis. The median survival of GBM patients is ∼15 months and there have not been any significant advance in therapies in over a decade, leaving treatment options limited. There is clearly an unmet need for GBM treatment. Immunotherapies are treatments based on usurping the power of the host's immune system to recognize and eliminate cancer cells. They have recently proven to be a successful strategy for combating a variety of cancers. Of the various types of immunotherapies, checkpoint blockade approaches have thus far produced significant clinical responses in several cancers including melanoma, non small-cell lung cancer, renal cancer, and prostate cancer. This review focuses on the biological rationale for using checkpoint blockade immunotherapeutic approaches in primary brain cancer and an up-to-date summary of current and ongoing checkpoint inhibitors-based clinical trials for malignant glioma. In addition, we expand on new concepts for further improving checkpoint blockade treatments, with a particular focus on the advantages of using genetically engineered mouse models for studies of immunotherapies in GBM. J. Cell. Biochem. 118: 2516-2527, 2017. © 2017 Wiley Periodicals, Inc.

Keywords: CANCER; CHECKPOINT INHIBITORS; GENETICALLY ENGINEERED MOUSE MODELS; GLIOBLASTOMA MULTIFORME.

Figure 1. Overview of multiple co-stimulatory and inhibitory pathways that regulate T cell responses

Schematic depiction of various ligand-receptor interactions between antigen-presenting cells (APCs) (or cancer cells) and T cells. These ligand-receptors complexes regulate T cell activation, either negatively or positively, in response to T cell receptor stimulation through an interaction with an antigen presented as a peptide-MHC molecule complex. Some of these ligand-receptor co-stimulatory and inhibitory complexes are expressed and active during initiation of naïve T cells in lymph nodes, where dendritic cells are considered the main APCs, whereas others are expressed and active in peripheral tissues or tumor cells where they regulate the effector responses of T cells. Note that many of these ligands bind to multiple receptors with opposite effect on TCR signaling. Different ligand-receptor complexes are expressed on the surface of various APCs as well as resting, naïve and activated T cells. They have distinct kinetics of expression and affinities for their cognate binding partners. The extent of T cell activation is proportional to the strength of the TCR signaling, which is dictated by a multitude of factors that are highly spatio temporal and context dependent. Abbreviations: APC, antigen-presenting cell; TIM-3, T cell– immunoglobulin–mucin domain 3; B7RP1, B7-related protein 1; BTLA, B and T lymphocyte attenuator; GAL9, galectin 9; HVEM, herpesvirus entry mediator; ICOS, inducible T cell co-stimulator; KIR, killer cell immunoglobulin- like receptor; LAG3, lymphocyte activation gene 3; PD1, programmed cell death protein 1; PDL, PD1 ligand