Targeting immune checkpoints in malignant glioma

Abstract

Malignant glioma is the most common and a highly aggressive cancer in the central nervous system (CNS). Cancer immunotherapy, strategies to boost the body's anti-cancer immune responses instead of directly targeting tumor cells, recently achieved great success in treating several human solid tumors. Although once considered "immune privileged" and devoid of normal immunological functions, CNS is now considered a promising target for cancer immunotherapy, featuring the recent progresses in neurobiology and neuroimmunology and a highly immunosuppressive state in malignant glioma. In this review, we focus on immune checkpoint inhibitors, specifically, antagonizing monoclonal antibodies for programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), and indoleamine 2,3-dioxygenase (IDO). We discuss advances in the working mechanisms of these immune checkpoint molecules, their status in malignant glioma, and current preclinical and clinical trials targeting these molecules in malignant glioma.

Keywords: CTLA-4; IDO; PD-1/PD-L1; immunotherapy; malignant glioma.

Figure 1. Immune checkpoints suppress T cell function in glioma microenvironment through differential mechanisms

A. The expression of PD-L1 on glioma cells is dependent on the PI3K-AKT pathway. PD-L1, upon engagement to its receptor PD-1 on T cells, inhibits activated T cell functions within the tumor microenvironment. B. CTLA-4 inhibits T cell activation. The co-stimulatory molecules from APCs, CD80 and CD86 bind to both stimulatory receptor CD28 and inhibitory receptor CTLA-4, yet with lower affinity to the former than to the latter. Therefore, CTLA-4 suppresses T cell activation via competitive inhibition. C. The maintenance, and function of T cells require adequate Trp levels, but IDO from tumor cells catabolizes Trp to numerous metabolites, such as Kyn. The decrease of Trp suppressed T cell activation. Meanwhile, the metabolites, such as Kyn can induced T cell apoptosis. D. In neurons surrounding glioma tissue, the expression of PD-L1 is induced by endogenous production of IFN-β. The neurons have the capability to inhibit proliferation of glioma cells and induce its apoptosis. Meanwhile, PD-L1+ neurons reduce the PD-L1 expression on glioma cells.

Figure 2. The diversified mechanisms by which various immune checkpoints promote each other, activate Tregs, and contribute to the immunosuppressive microenvironment in glioma

A. IDO from tumor cells catabolizes Trp to Kyn. PD-1/PD-L1 pathway and Kyn could induce FoxP3 expression and promote Treg conversion with the assistance of TGF-β. B. FoxP3 controls CTLA-4 expression by Tregs. The CTLA-4 on Tregs binds to CD80/86, up-regulates the expression of IDO, down-regulates the expression of CD80 and CD86 on APCs, and enhances the suppressive functions of Tregs.