IMMU-50. THE IMMUNE LANDSCAPE OF BLOOD DENDRITIC CELLS IN GLIOBLASTOMA MULTIFORME: IMPLICATIONS FOR DC VACCINATION COMBINED WITH CHECKPOINT INHIBITION

Abstract

Therapeutic dendritic cell vaccination for GBM using primary blood dendritic cells (BDC) has the potential to improve response rates compared with more commonly used monocyte-derived dendritic cells due to their superior antigen-presentation and migration. Combination of vaccination with immune checkpoint inhibitors such as anti-PD-1 antibodies may remove tumour-associated immune suppression and directly enhance DC function. GBM is associated with systemic as well as local immune suppression. Therefore it is critical to understand the immune landscape and effect of current treatments on DC function and modulate this to successfully translate vaccination into patients. To that end, we firstly compared the expression of immune checkpoint molecules (PD-1, CTLA-4, TIM-3, LAG-3, ICOS, CD27 axes) on BDC (DC1, DC 2/3, DC6) and lymphocyte subsets (CD3+, CD4+, CD8+, CD56+, Treg) from newly diagnosed or currently treated GBM patients (GBM) with age-matched healthy donors (HD) using flow cytometry. This analysis revealed that the major BDC subsets were identifiable in HD and GBM but were affected by both corticosteroids and concurrent chemoradiation. Furthermore, phenotypic differences exist between HD and GBM, most notably in expression of PD-L2 by BDC. We tested the functional capacity of CD1c+ BDC from HD and GBM patients. After optimizing the maturation process of CD1c+ BDC, their ability to initiate polyclonal immune responses was determined using one-way mixed leucocyte reactions. To further augment vaccine efficacy and overcome tumour-associated immune suppression, we combined this with immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4 antibodies. BDC were loaded with the glioma antigen, CMV-pp65 protein to demonstrate the combined effect of immune checkpoint blockade on cytokine production by intracellular staining, antigen-specific T cell expansion and cytotoxicity. DC vaccination in GBM with BDC is a feasible, rational combination with immune checkpoint inhibitors which enhances cytotoxicity in an antigen-specific fashion.