Abstract 4751: Peptide vaccine induces apoptosis of antigen-specific CD8⁺ T cells

Abstract

CD8⁺ cytotoxic T lymphocytes (CTL) play a critical role in anti-tumor immunity. Although multiple trials of cancer vaccines, particularly using short peptides recognized by CD8⁺ T cells, have resulted in the development of measurable immune responses, only a minority of patients has experienced clinical benefit such as tumor regression. On the other hand, accumulating data show that peptide immunization induces either tolerance or activation of peptide-specific T cells depending on doses, routes and frequency of peptide administration. In some experiments, vaccination with peptides recognized by CD8⁺ T cells caused enhanced tumor outgrowth associated with peptide-induced tolerance. However, the detailed mechanism(s) involved in this unfavorable immune response by peptide vaccinations has not been determined. In the present study, we analyzed NY-ESO-1 peptide vaccinations using a new tumor model of BALB/c transplanted tumors expressing NY-ESO-1, which is a cancer/testis (CT) antigen discovered by SEREX (serological identification of antigens by recombinant expression cloning) using the serum of an esophageal cancer patient. Whereas peptide immunization with an H2-D^d-restricted CTL epitope derived from NY-ESO-1 (NY-ESO-1 p81-88) induced NY-ESO-1_81–88-specific CD8⁺ T cells in draining lymph nodes and spleens, tumor growth was significantly enhanced. Single cell analysis of specific CD8⁺ T cells revealed that peptide immunization induced apoptosis of > 80% of NY-ESO-1_81–88-specific CD8⁺ T cells at tumor sites and repetitive immunization further diminished the number of specific CD8⁺ T cells. This phenomenon was associated with elevated surface expression of Fas and PD-1. When peptide vaccination was combined with an adjuvant, a TLR9 ligand CpG, the elevated Fas and PD-1 expression and apoptosis induction were not observed, and resulted in strong tumor growth inhibition. These augmented anti-tumor responses were correlated with CpG-induced DC maturation, as CpG-matured DCs, but not immature DCs could reduced Fas and PD-1 expression on the surface of antigen-specific CD8⁺ T cells. Taken together, selection of appropriate adjuvants is essential for development of effective cancer vaccines, with protection of effector T cells from peptide vaccine-induced apoptosis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4751.