Introduction: Immunosuppressive myeloid cells are elevated in the tumors and peripheral circulation of glioblastoma (GBM) patients. Programmed death-ligand 1 (PD-L1), expressed on myeloid derived suppressor cells (MDSCs) and other monocyte populations, contributes to immune suppression through induction of T cell apoptosis and anergy. GBM secreted factors can increase PD-L1 expression in naïve monocytes. However, it remains unknown to what extent GBM derived factors differentially induce PD-L1 on MDSCs and non-MDSCs.
Methods: Preoperative peripheral blood mononuclear cells from newly diagnosed GBM patients (n = 34) were collected and analyzed by flow cytometry for PD-L1+ MDSCs (CD11b+CD33+HLA-DRlo/-PD-L1+) and non-MDSC monocytes (CD11b+CD33+HLA-DRhiPD-L1+). To investigate the role of GBM secreted factors in MDSC and non-MDSC PD-L1 induction, naïve monocytes were isolated from healthy donor blood and stimulated with GBM-conditioned media (n = 6) for 24 hours before analysis.
Results: The median MDSC frequency in GBM patient peripheral blood was 14.6% of total myeloid cells. Median PD-L1 expression on MDSCs was 46.9%, which was lower than the median PD-L1 expression on non-MDSC monocytes of 64.2% (p < 0.05). Whereas MDSC and monocyte PD-L1 expression were positively correlated (p < 0.0001, R2 = 0.739), MDSC abundance and MDSC PD-L1 expression were not correlated (p = 0.77, R2 = 0.003). MDSCs isolated from healthy donors exhibited a 2.8-fold (95% CI: 2.5-3.1) increased baseline PD-L1 expression compared to monocytes. Upon stimulation with GBM-conditioned media, however, monocytes demonstrated a 2.2-fold (95% CI: 1.9-2.4) increased PD-L1 induction (relative to baseline), compared to a minimal 1.1-fold (95% CI: 1.0-1.2) increase observed in MDSCs (p < 0.001).
Conclusions: Although MDSCs exhibit higher baseline PD-L1 expression, non-MDSC monocytes demonstrate greater inducible PD-L1 potential. Moreover, as non-MDSCs comprise a greater proportion of myeloid cells and express elevated PD-L1 in GBM patients, the blockade of PD-L1 induction in this population may serve as a mechanism to improve GBM immunotherapy.
Patient Care: Identification of non-MDSC monocytes as the predominant inducible PD-L1 population in GBM patients provides a rationale for investigating the blockade of PD-L1 induction in this population as a means to improve immunotherapy for GBM.
Learning Objectives: By the conclusion of the session, participants should be able to (1) identify GBM secreted factors as drivers of PD-L1 expression on myeloid cells and (2) identify non-MDSCs and MDSCs as having different PD-L1 induction potentials.
References: Raychaudhuri B, Rayman P, Ireland J, Ko J, Rini B, Borden EC, Garcia J, Vogelbaum MA, Finke J. Myeloid-derived suppressor cell accumulation in patients with newly diagnosed glioblastoma. Neuro Onc 2011; 13(6): 591-599.
Rodrigues JC, Gonzalez GC, Zhang L, Ibrahim G, Kelly JJ, Gustafson MP, Lin Y, Dietz AB, Forsyth PA, Yong VW, Parney IF. Normal human monocytes exposed to glioma cells acquire myeloid-derived suppressor cell-like properties. Neuro Onc 2010; 12(4): 351-365.
Gustafson MP, Lin Y, New KC, Bulur PA, O'Neill P, Gastineau DA, Dietz AB. Systemic immune suppression in glioblastoma: the interplay between CD14+HLA-DRlo/neg monocytes, tumor factors, and dexamethasone. Neuro Onc 2010; 12(7): 631-644.