Dynamic CD8 T-cell responses to tumor-associated Epstein-Barr virus (EBV) antigens in patients with EBV-negative Hodgkin's disease

Abstract

8573 Background: Multiple translational efforts in HD are actively investigating augmentation of the anti-tumor immune response by stimulating cytotoxic T lymphocytes (CTL) against tumor-associated EBV antigens. It has previously been believed that this therapeutic strategy and presence of EBV-specific CTLs are limited to EBV-positive HD. Here, we challenge this belief by characterizing EBV-specific CTL responses in EBV-negative HD. Methods: Among 52 consecutive patients with EBV-negative HD, CTL responses to latent antigens (LMP2, LMP2a) and lytic antigens (BMLF, BRLF) were serially assessed at diagnosis, during chemotherapy, and throughout followup for 2 years by IFN-γ Elispot and flow cytometric tetramer analysis. Results: We detected weak EBV-specific responses to both lytic and latent antigens by IFN-γ Elispot among patients with EBV-negative HD. Response to lytic antigen, BMLF1, was more robust in function and size among healthy donors compared to patients as determined by IFN-γ Elispot and flow cytometry of BMLF1-tetramer positive, CD8 T cells. Chemoradiotherapy was associated temporally with an initial decrease in LMP2A- and BMLF1-specific responses during the first 5–15 weeks of treatment, which subsequently became more robust 20–50 weeks after diagnosis, 2 to 4-fold greater compared to response at diagnosis. At final follow-up (24 months), increases in both lytic (2.6-fold) and latent (2.5-fold) CTL responses were observed with robustness of lytic-specific response equivalent to healthy controls. No significant change in control peptide response was observed. Conclusions: We confirm evidence of EBV-specific CTLs in patients with EBV-negative HD and provide the first report of dynamic variance in this population during treatment, challenging prior belief that patients with HD remain immunodeficient following therapy and arguing that the clinical significance of EBV-specific immune responses in EBV-negative HD should be further investigated. [Table: see text] No significant financial relationships to disclose.