High-grade glioma associated immunosuppression does not prevent immune responses induced by therapeutic vaccines in combination with Treg depletion

Abstract

High-grade gliomas (HGG) exert systemic immunosuppression, which is of particular importance as immunotherapeutic strategies such as therapeutic vaccines are increasingly used to treat HGGs. In a first cohort of 61 HGG patients we evaluated a panel of 30 hematological and 34 plasma biomarkers. Then, we investigated in a second cohort of 11 relapsed HGG patients receiving immunomodulation with metronomic cyclophosphamide upfront to a DC-based vaccine whether immune abnormalities persisted and whether they hampered induction of IFNγ+ T-cell responses. HGG patients from the first cohort showed increased numbers of leukocytes, neutrophils and MDSCs and in parallel reduced numbers of CD4+/CD8+ T-cells, plasmacytoid and conventional DC2s. MDSCs and T-cell alterations were more profound in WHO IV° glioma patients. Moreover, levels of MDSCs and epidermal growth factor were negatively associated with survival. Serum levels of IL-2, IL-4, IL-5 and IL-10 were altered in HGG patients, however, without any impact on clinical outcome. In the immunotherapy cohort, 6-month overall survival was 100%. Metronomic cyclophosphamide led to > 40% reduction of regulatory T cells (Treg). In parallel to Treg-depletion, MDSCs and DC subsets became indistinguishable from healthy controls, whereas T-lymphopenia persisted. Despite low T-cells, IFNγ-responses could be induced in 9/10 analyzed cases. Importantly, frequency of CD8+VLA-4+ T-cells with CNS-homing properties, but not of CD4+ VLA-4+ T-cells, increased during vaccination. Our study identifies several features of systemic immunosuppression in HGGs. Metronomic cyclophosphamide in combination with an active immunization alleviates the latter and the combined treatment allows induction of a high rate of anti-glioma immune responses.Electronic supplementary materialThe online version of this article (10.1007/s00262-018-2214-0) contains supplementary material, which is available to authorized users.

The Paired Siglecs in Brain Tumours Therapy: The Immunomodulatory Effect of Dexamethasone and Temozolomide in Human Glioma In Vitro Model

“…The tumour-controlled extracellular communication is critical to promote the progression switch mechanisms and diminish antitumor processes, including immune surveillance [ 3 , 4 ]. In response to the tumour-derived factors, both, resident and peripheral immune cells, including CD4 + regulatory T cells (Tregs), eosinophiles, monocytes and resident microglia, undergo reprogramming that results in altered secretory capacity and phagocytic functions [ 4 , 5 , 6 , 7 ]. The crosstalk between glioma cells and the heterogenic immune population is mediated by suppressive cytokines that disturb the balance of proliferation and apoptosis, and switch the activity phenotype from M1 to M2.…”

Blood-Based Biomarkers for Glioma in the Context of Gliomagenesis: A Systematic Review

“…Accuracies of AUC = 0.9-1.0 (13) and a sensitivity 95% and specificity of 85% (19), have been found. However, IL-1b (21,24) and IL-6 (21,22,25,26) concentrations were also found to not be changed compared to controls or even decreased in glioma patients compared to FIGURE 2 | Overview of possible blood-based biomarkers for glioma and their purposes. Schematic overview of the several biosources (plasma, serum, extracellular vesicles, blood platelets, circulating immune cells, and circulating glioma tumor cells) and biomolecules (proteins, nucleic acids, metabolomics and peptides) that are identified for patients with glioma.…”

“…In glioma patients it was often observed that WBC counts were increased compared to controls (21,54,55,100,118,220). However, it was also found that leukocytes are not significantly changed in glioma patients compared to controls (21,194), potentially due to dexamethasone use (221)(222)(223)(224).…”

Prostaglandin E2 in a TLR3- and 7/8-agonist-based DC maturation cocktail generates mature, cytokine-producing, migratory DCs but impairs antigen cross-presentation to CD8+ T cells

“…Altogether, these data led to removal of PGE 2 from DC maturation cocktails by several groups [11]. In our own brain tumor vaccination program, we have used TNFα and IL-1ß as maturing agents so far and validated this combination as the standard for generation of clinical-grade DCs under GMP [12,13].…”