The Role of Oxygen in the Immunogenicity of brain tumor cell vaccines

Abstract

Tumor cell vaccination is a promising strategy for patients with primary brain tumors. Cell-derived vaccines have been developed and tested in patients with many cancers, resulting in objective responses in a minority of cases. Tumor cells are often harvested from tissue culture, where phenotype can shift in response to many factors. Oxygen affects expression of thousands of genes, yet its impact on immunogenicity in culture was unknown until recently. Compared to atmospheric oxygen levels, physiologic (5%) oxygen increases the adjuvant properties and efficacy of glioma vaccines. These studies determined the impact of oxygen on cell-mediated and humoral immunity with regard to its potential for improving efficacy in brain tumor patients. Immunogenicity and oxygen were first investigated over a broader oxygen range, with 5% oxygen still yielding the greatest extension of survival. With the effort to maximize immunogenicity, primary autologous meningioma cells from pet dogs were cultured in 5% oxygen for vaccine production. Dogs vaccinated with lysate/adjuvant vaccines based on these cells induced robust antibody responses and survived a median of three-fold longer than historic controls. Further studies in mice led to the discovery that glioma cells cultured in 5% oxygen upregulated a "danger" signal, annexin II. Monomeric annexin II enhanced dendritic cell cross presentation, CD8 T cell priming, and extended survival of murine breast carcinoma and plasmacytoma. Enriching for endogenous danger signals by decreasing tissue culture oxygen is a simple means to enhance the immunogenicity of brain tumor cultures.