T Cell Exhaustion in Glioblastoma: Intricacies of Immune Checkpoints. Issue 2 (February 2017) - Mirzaei, Reza
Abstract : Glioblastoma is an aggressive and incurable primary brain tumor. While the blockade of immune checkpoints leads to reversal of T cell exhaustion in many cancers, the efficacy of this therapy in glioblastoma requires further consideration of the brain microenvironment beyond T cell activity. Neural cells are crucially dependent on glucose for survival, and tumor cells rabidly consume glucose; the glucose-deprived microenvironment further elevates immune checkpoint molecules to benefit tumor growth and exacerbate T cell exhaustion. We review here how immune checkpoints drive exhaustion in T cells while favoring tumor metabolism, and discuss how glucose competition in the unique CNS milieu is an important consideration to improve the outcomes of immune checkpoint blockade in glioblastoma. Trends: Vigorous competition for glucose takes place in the brain tumor microenvironment between neurons, T cells, and transformed cells. This competition affects tumor progression. There is a robust association between immune checkpoint expression and the metabolic profile of different cell types in the tumor microenvironment. Immune checkpoint molecules limit glycolysis in T cells while increasing that in tumor cells. Immune checkpoint blockade in glioblastoma should be directed not only to T cells but also to the corresponding ligands on transformed cells that promote tumor metabolism. In addition to tumor characteristics such as mutational load, the expression of immune checkpoints, T cell density, and local glycolytic profile are additional considerations in glioblastoma. These interacting factors need further attention to improve the clinical outcome of immune checkpoint blockade.