Glioblastoma patients exhibit circulating tumor-specific CD8+ T cells

Abstract

Purpose: There is growing interest in developing cellular immune therapies for glioblastoma multiforme, but little is known about tumor-specific T-cell responses. A glioblastoma multiforme-specific T-cell assay was developed using monocyte-derived dendritic cells to present tumor antigens from the established glioblastoma multiforme cell line U118. Experimental Design: Peripheral blood mononuclear cells (PBMC) and tumor cells were obtained from nine patients with newly diagnosed brain tumors: five glioblastoma multiforme, two oligodendroglioma, one ependymoma, and one astrocytoma. PBMCs were incubated overnight with autologous tumor cells or autologous dendritic cells loaded with a U118 cell lysate, and responses were detected by IFN-γ ELISPOT and cytokine flow cytometry assays. Results: PBMCs from all glioblastoma multiforme patients exhibited IFN-γ responses to autologous tumor but not to HLA-mismatched U118 cells. Glioblastoma multiforme-specific IFN-γ responses were primarily mediated by CD8+ Tcells and represented ≃ 2% of total CD8+ T cells. Additionally, all glioblastoma multiforme patients responded to autologous dendritic cells loaded with U118 lysate but not with low-grade astrocytoma cell lysates. PBMCs from four patients with other brain tumor types and one normal donor failed to respond to U118 lysate- loaded autologous dendritic cells. These data indicate that the IFN-γ responses to U118 lysate - loaded autologous dendritic cells are glioblastoma multiforme specific. Moreover, PBMCs stimulated 1 to 2 weeks with U118 lysate-loaded dendritic cells exhibited MHC class I-restricted cytotoxicity against autologous tumor cells. Conclusions: Glioblastoma multiforme patients exhibit circulating tumor-specific CD8+ T cells that recognize shared tumor antigens from the glioblastoma multiforme cell line U118. These data show that glioblastoma multiformes are immunogenic and support the development of immunotherapy trials. © 2005 American Association for Cancer Research.