Adjuvants that improve the ratio of antigen-specific effector to regulatory T cells enhance tumor immunity

Abstract

Antitumor immunity is strongly influenced by the balance of tumor antigen-specific effector T cells (Teff) and regulatory T cells (Treg). However, the impact that vaccine adjuvants have in regulating the balance of antigen-specific T-cell populations is not well understood. We found that antigen-specific Tregs were induced following subcutaneous vaccination with either OVA or melanoma-derived peptides, with a restricted expansion of Teffs. Addition of the adjuvants CpG-ODN or Poly(I:C) preferentially amplified Teffs over Tregs, dramatically increasing the antigen-specific Teff:Treg ratios and inducing polyfunctional effector cells. In contrast, two other adjuvants, imiquimod and Quil A saponin, favored an expansion of antigen-specific Tregs and failed to increase Teff:Treg ratios. Following therapeutic vaccination of tumor-bearing mice, high ratios of tumor-specific Teffs:Tregs in draining lymph nodes were associated with enhanced CD8(+) T-cell infiltration at the tumor site and a durable rejection of tumors. Vaccine formulations of peptide+CpG-ODN or Poly(I:C) induced selective production of proinflammatory type I cytokines early after vaccination. This environment promoted CD8(+) and CD4(+) Teff expansion over that of antigen-specific Tregs, tipping the Teff to Treg balance to favor effector cells. Our findings advance understanding of the influence of different adjuvants on T-cell populations, facilitating the rational design of more effective cancer vaccines.