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.
Highlights
More than four decades ago, Brooks and colleagues reported about reduced lymphocyte function in patients with intracranial tumors [3]
Leukocyte and neutrophil numbers were significantly increased in high-grade glioma (HGG) patients; significance was only reached for WHO IV° patients (Fig. 1a)
Systemic immunosuppression may hinder the development of anti-tumor immune responses, as priming of glioma-specific cytotoxic T-cells has to occur outside the CNS in secondary lymphatic organs
Summary
More than four decades ago, Brooks and colleagues reported about reduced lymphocyte function in patients with intracranial tumors [3]. Inhibitory features of glioma cells can result in either systemic or local immunosuppression. Whereas the latter mainly impedes the effector phase of anticancer immunity, systemic immunosuppression represents a major hurdle against a successful priming of glioma-directed immune responses. An altered composition of the leukocyte compartment with an increased neutrophil/ lymphocyte ratio [4] and increased frequencies of MDSCs in peripheral blood have been reported [5,6,7]. In murine glioma models it could be demonstrated that interference with immunosuppression like depletion or inhibition of regulatory T-cells (Treg) and MDSCs is associated with reduced gliomagenesis, increased antitumor immune responses and improved survival [11,12,13]
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