Enhancing T Cell Chemotaxis and Infiltration in Glioblastoma

Glioblastoma is an immunologically 'cold' tumor, which are characterized by absent or minimal numbers of tumor-infiltrating lymphocytes (TILs). For those tumors that have been invaded by lymphocytes, they are profoundly exhausted and ineffective. While many immunotherapy approaches seek to reinvigorate immune cells at the tumor, this requires TILs to be present. Therefore, to unleash the full potential of immunotherapy in glioblastoma, the trafficking of lymphocytes to the tumor is highly desirable. However, the process of T cell recruitment into the central nervous system (CNS) is tightly regulated. Naive T cells may undergo an initial licensing process to enter the migratory phenotype necessary to enter the CNS. T cells then must express appropriate integrins and selectin ligands to interact with transmembrane proteins at the blood-brain barrier (BBB). Finally, they must interact with antigen-presenting cells and undergo further licensing to enter the parenchyma. These T cells must then navigate the tumor microenvironment, which is rich in immunosuppressive factors. Altered tumoral metabolism also interferes with T cell motility. In this review, we will describe these processes and their mediators, along with potential therapeutic approaches to enhance trafficking. We also discuss safety considerations for such approaches as well as potential counteragents.

Automated summary

Glioblastoma is an immunologically 'cold' tumor characterized by low or absent numbers of tumor-infiltrating lymphocytes, which if present are exhausted and ineffective. To maximize immunotherapy efficacy in glioblastoma, it is highly desirable to enhance the trafficking of lymphocytes to the tumor. However, the process of T cell recruitment into the central nervous system is tightly regulated, involving multiple steps including interaction with the blood-brain barrier and navigating the tumor microenvironment.