Expression of PD-1 by T Cells in Malignant Glioma Patients Reflects Exhaustion and Activation.

Abstract

Glioblastoma (GBM) is the most common primary malignant tumor in the central nervous system. Our recent preclinical work has suggested that PD-1/PD-L1 plays an important immunoregulatory role to limit effective antitumor T-cell responses induced by active immunotherapy. However, little is known about the functional role that PD-1 plays on human T lymphocytes in patients with malignant glioma.<b>Experimental Design:</b> In this study, we examined the immune landscape and function of PD-1 expression by T cells from tumor and peripheral blood in patients with malignant glioma. We found several differences between PD-1⁺ tumor-infiltrating lymphocytes (TIL) and patient-matched PD-1⁺ peripheral blood T lymphocytes. Phenotypically, PD-1⁺ TILs exhibited higher expression of markers of activation and exhaustion than peripheral blood PD-1⁺ T cells, which instead had increased markers of memory. A comparison of the T-cell receptor variable chain populations revealed decreased diversity in T cells that expressed PD-1, regardless of the location obtained. Functionally, peripheral blood PD-1⁺ T cells had a significantly increased proliferative capacity upon activation compared with PD-1^- T cells. Our evidence suggests that PD-1 expression in patients with glioma reflects chronically activated effector T cells that display hallmarks of memory and exhaustion depending on its anatomic location. The decreased diversity in PD-1⁺ T cells suggests that the PD-1-expressing population has a narrower range of cognate antigen targets compared with the PD-1 nonexpression population. This information can be used to inform how we interpret immune responses to PD-1-blocking therapies or other immunotherapies.