Spontaneous immune responses against glioma-associated antigens in a long term survivor with malignant glioma

Background: In patients with high grade glioma, little is known regarding existence of naturally occurring adaptive T cell reactivity against glioma-associated antigens (GAAs). In this report, we characterized GAA-specific CD8(+) T cells and innate immune cells in a patient who has survived with anaplastic astrocytoma (AA) for over 12 years without recurrence. Methods: Peripheral blood mononuclear cells (PBMCs) derived from the long term survivor with AA were evaluated for the frequency, cytotoxic T lymphocyte (CTL) activity and differentiation status of CD8(+) cells recognizing GAA-derived epitopes as well as relative numbers of other immune cell subsets. This patient's AA tissue was evaluated for expression of two GAAs EphA2 and interleukin-13 receptor alpha 2 subunit (IL-13R alpha 2) by immunohistochemistry. Results: The patient's tumor expressed both EphA2 and IL-13R alpha 2, and in vitro stimulated PBMC demonstrated superior EphA2(883-891) and IL- 13R alpha 2(345-353)-specific CTL reactivity compared to PBMC samples from two other patients with progressing malignant glioma. Unstimulated EphA2(883-891)- reactive CD8(+) T cells contained high numbers of CD45RA-/CCR7-late effector and CD45RA-/ CCR7(+) central memory cells. Among other leukocyte subsets, elevated numbers of NK-T cells were found. Conclusion: To our knowledge, the current study is one of the first demonstrating the presence of antigen-experienced, GAA-reactive CD8(+) T cells in a patient who has survived with AA for over 12 years without recurrence. Further studies are warranted to determine whether the status of GAA-reactive CD8(+) T cells dictates survival of patients and/or response to therapeutic vaccines.