The immune checkpoint protein PD-L1 induces and maintains regulatory T cells in glioblastoma
| Autor: | Gurvinder Kaur, Winward Choy, Leonel Ampie, Yuping Li, Joseph D. DiDomenico, Jason B. Lamano, Orin Bloch, Jonathan B. Lamano, Dorina Veliceasa, Daniel E. Oyon |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
lcsh:Immunologic diseases. Allergy Regulatory T cell medicine.medical_treatment Immunology Oncology and Carcinogenesis chemical and pharmacologic phenomena regulatory t cell lcsh:RC254-282 03 medical and health sciences Rare Diseases Downregulation and upregulation Clinical Research PD-L1 medicine Immunology and Allergy 2.1 Biological and endogenous factors Aetiology Original Research Cancer nivolumab immunosuppression biology business.industry Neurosciences glioblastoma pd-1 Immunosuppression hemic and immune systems Immunotherapy medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Immune checkpoint nervous system diseases Brain Disorders Brain Cancer 030104 developmental biology medicine.anatomical_structure Oncology pd-11 Cancer research biology.protein immunotherapy Nivolumab business lcsh:RC581-607 Glioblastoma |
| Zdroj: | OncoImmunology, Vol 7, Iss 7 (2018) Oncoimmunology, vol 7, iss 7 |
| Popis: | Glioblastoma (GBM) promotes immunosuppression through upregulation of PD-L1 and regulatory T cell (Treg) expansion, but the association of these suppressive factors has not been well elucidated. Here, we investigate a role of PD-L1 in expanding Tregs and the value of targeting the PD-1 receptor to inhibit Treg expansion. Quantitative RNA sequencing data from The Cancer Genome Atlas were evaluated for an association between CD274 and FOXP3 transcript expressions and impact of FOXP3 on clinical outcomes. Peripheral leukocytes from patients with newly diagnosed GBM were profiled for PD-L1+ myeloid expressions and Treg abundance. Healthy lymphocytes were assessed for impact of recombinant PD-L1 on expansion of the inducible Treg (iTreg) population. iTreg function was evaluated by the capacity to suppress effector T cell proliferation. Specificity of responses were confirmed by pharmacologic inhibition of the PD-1 receptor. Increased PD-L1 mRNA expression in GBM corresponded to increased FOXP3 mRNA (p = 0.028). FOXP3 elevation had a negative impact on overall survival (HR = 2.0; p < 0.001). Peripheral PD-L1 positivity was associated with an increased Treg fraction (p = 0.008). Lymphocyte activation with PD-L1co-stimulation resulted in greater iTreg expansion compared to activation alone (18.3% vs. 6.5%; p < 0.001) and improved preservation of the Treg phenotype. Suppressive capacity on naïve T cell proliferation was sustained. Nivolumab inhibited PD-L1-induced Treg expansion (p < 0.001). These results suggest that PD-L1 may expand and maintain immunosuppressive Tregs, which are associated with decreased survival in glioma patients. Blockade of the PD-L1/PD-1 axis may reduce Treg expansion and further improve T cell function beyond the direct impact on effector cells. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|