Blocking immunosuppressive checkpoints for glioma therapy: the more the Merrier!

Abstract

Immunosuppressive checkpoints mediated by IDO, CTLA4, and PD1/PDL1 play a critical role in glioma progression and the efficacy of immunotherapies. Combined blockade of these immunosuppressive checkpoints in a glioma model elicited long-term survival. This combined blockade adds to the armamentarium of anti-glioma therapies, which could be implemented in clinical trials. Clin Cancer Res; 20(20); 5147-9. ©2014 AACR.

Figure 1

Molecular targets and associated therapies to block three immunosuppressive checkpoints in a malignant brain tumor (glioma) model. Glioma cells overexpress IDO to convert l-tryptophan to N′-formyl-kynurenine, the first step in the kynurenine metabolic pathway, which induces the accumulation of immunosuppressive Tregs in the tumor microenvironment. Therapy 1, the tryptophan analog, 1-MT, used as an IDO-specific competitive inhibitor. CD80 molecules on the surface of antigen-presenting cells (i.e., APC) interact with CTLA4 on the T-cell surface in the context of antigen-presenting MHC class I, inhibiting T-cell activation and decreasing proliferation, resulting in suppressed antitumor effector function. Therapy 2, anti-CTLA4 monoclonal antibodies bind to CTLA4, inhibiting its immunosuppressive signal, while promoting the interaction of CD80 with CD28, a T cell–activating receptor. Glioma cells express PDL1, which interacts with its cognate receptor PD1 on the T-cell surface to downregulate tumor lytic capacity and promote T-cell anergy in the context of tumor antigen-presenting MHC class I. Therapy 3, anti-PDL1 monoclonal antibodies bind to PDL1 on the surface of tumor cells to enable T cells to remain in an activated state characterized by high tumor lytic capacity and increased proliferation.