Adjuvants that improve the ratio of antigen-specific effector to regulatory T cells enhance tumor immunity.
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.
Authors' Affiliation: Ludwig Center for Cancer Research, University of Lausanne, Lausanne, Switzerland.
Rachel
R
Perret
Sophie R
SR
Sierro
Natalia K
NK
Botelho
Stéphanie
S
Corgnac
Alena
A
Donda
Pedro
P
Romero
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000941:Antigens / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage; D005260:Female; D007111:Immunity, Cellular / Q000187:drug effects*; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D037182:T-Cell Antigen Receptor Specificity / Q000187:drug effects*; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D000941:Antigens; D019496:Cancer Vaccines