Abstract 4846: Histamine in myeloid cell maturation and malignant glioma development
Authors: Ahn Brian , Kohanbash Gary , Kosaka Akemi , Ohkuri Takayuki , Okada Hideho 
Published: May 2015

Abstract
Multiple epidemiological studies have demonstrated an association between allergic conditions and protection from glioma development. Also, use of anti-histamines has shown up to a 3.5-fold increase in the risk of malignant glioma. Previous studies have shown deviations in myeloid cell maturation in mice deficient for histidine decarboxylase (HDC-/-), the key enzyme in histamine production. HDC-/- mice exhibited increased levels of CD11b+GR1+ immature myeloid cells (IMC). This cellular phenotype is associated with myeloid-derived suppressor cells (MDSC), which are thought to be IMC that can inhibit T cell function and have been shown to promote tumor development. From this data, we hypothesize that histamine is important to normal myeloid maturation, whereas a lack thereof can promote accumulation of immunosuppressive IMC, which can stimulate glioma development.
Utilizing our de novo tumor model, we observed faster tumor induction as well as increased growth in the HDC-/- mice compared to wild type (WT). Also, HDC-/- mice exhibited decreased symptom-free survival (SFS) compared to WT (74 vs 86 days, respectively; p=0.04). Analysis of brain-infiltrating leukocytes (BIL) a time of symptoms demonstrated increased frequency of CD11b+Gr1+ IMC in HDC-/- mice compared to WT (52% vs 34%; p=0.02). While not reaching statistical significance, there was a trend towards increased CD11b+GrLo compartment (28% vs 11%; p=0.08).
Furthermore, SB-derived glioma cell lines from both HDC-/- and WT mice were generated. No significant differences were observed in in vitro growth dependent upon HDC expression or histamine concentration. These cell lines were utilized for in vivo studies via intracranial orthotopic injections. No differences in survival or growth were observed when HDC-expressing cell lines were utilized, whereas significantly increased tumor volume at day 14 and decreased SFS was observed in HDC-/- mice compared to WT when the HDC-/- glioma cells were used (15 vs 23 days; p=0.04). HDC-/- mice exhibited increased CD11b+Gr1Lo compared to WT in the BIL (45% vs 28%; p=0.03). Also, HDC-/- mice possessed decreased CD8+CD107a+ cells at the tumor site, suggesting a decreased T cell response in the absence of histamine. This data suggests a more crucial role for local compared to systemic histamine on glioma development.
Additionally, we believe that the presence of glioma can inhibit HDC expression further leading to the accumulation of IMC. By use of HDC-eGFP mice, in vitro studies showed that the addition of glioma supernatant prevented the upregulation of HDC in bone marrow cells by growth factors. In vivo HDC expression in CD11b+Gr1+ myeloid cells was decreased in bone marrow, spleen, and BIL in mice with glioma compared to non-tumor bearing mice. These collective data suggest that disruption of histamine signaling can promote glioma development by augmenting the accumulation of immunosuppressive IMC leading to decreased T cell response.
Citation Format: Brian Ahn, Gary Kohanbash, Akemi Kosaka, Takayuki Ohkuri, Hideho Okada. Histamine in myeloid cell maturation and malignant glioma development. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4846. doi:10.1158/1538-7445.AM2014-4846