Journal
CLINICAL CANCER RESEARCH
Volume 25, Issue 6, Pages 1913-1922Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-18-1176
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Funding
- NIH/NCI [R21-CA186004, R01CA154256, RO1 CA125244, KL2 ULITR001881, R25 NS079198]
- UCLA SPORE in Brain Cancer [P50 CA211015]
- Parker Institute for Cancer Immunotherapy (PICI) [20163828]
- Musella Foundation for Brain Tumor Research
- Joseph Drown Foundation
- UCLA Children's Discovery and Innovation Institute Today's and Tomorrow's Children Fund (TTCF)
- UCLA Medical Scientist Training Program (MSTP)
- UCLA Tumor Immunology Training Grant (USHHS Ruth L. Kirschstein Institutional National Research Service Award) [T32 CA009056]
- NIH [P30 CA016042, 5P30 AI028697]
- [CURE/P30DK41301]
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Purpose: 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 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 patients with malignant glioma. Experimental Design: 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. Results: 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. Conclusions: 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.
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