Expression of PD-1 by T cells in malignant glioma patients reflects exhaustion and activation

Purpose: Glioblastoma (GBM) is the most common primary malignant tumor in the central nervous system. Our recent pre-clinical work has suggested that PD-1/PD-L1 plays an important immunoregulatory role to limit effective anti-tumor T cell responses induced by active immunotherapy. However, little is known about the functional role that PD-1 plays on human T lymphocytes in malignant glioma patients. Experimental Design: In this study, we examined the immune landscape and function of PD-1 expression on T cells from the tumor and peripheral blood in malignant glioma patients. Results: We found several differences between PD-1+ tumor-infiltrating lymphocytes (TILs) 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. Conclusion: Our evidence suggests that PD-1 expression in glioma patients reflects chronically-activated effector T cells that display hallmarks of memory and exhaustion depending on its anatomical 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 to the PD-1 non-expression population. This information can be used to inform how we interpret immune responses to PD-1 blocking therapies or other immunotherapies.

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