Abstract
While showing promise, vaccination strategies to treat cancer require further optimization. Likely barriers to efficacy involve cancer-associated immunosuppression and peripheral tolerance, which limit the generation of effective vaccine-specific cytotoxic T lymphocytes (CTL). Because CD4(+) T cells improve CTL responsiveness, next-generation vaccines include helper epitopes. Here, we demonstrate in mice how CD4(+) T-cell help optimizes the CTL response to a clinically relevant DNA vaccine engineered to combat human papillomavirus-expressing tumors. Inclusion of tumor-unrelated helper epitopes greatly increased CTL priming, effector, and memory T-cell programming. CD4(+) T-cell help optimized the CTL response in all these aspects via CD27/CD70 costimulation. Notably, administration of an agonistic CD27 antibody could largely replace helper epitopes in promoting primary and memory CTL responses, acting directly on CD8(+) T cells. CD27 agonism improved efficacy of the vaccine without helper epitopes, more so than combined PD-1 and CTLA-4 blockade. Combining CD27 agonism with CTLA-4 blockade improved vaccine-induced CTL priming and tumor infiltration, but only combination with PD-1 blockade was effective at eradicating tumors, thereby fully recapitulating the effect of CD4(+) T-cell help on vaccine efficacy. PD-1 blockade alone did not affect CTL priming or tumor infiltration, so these results implied that it cooperated with CD4(+) T-cell help by alleviating immune suppression against CTL in the tumor. Helper epitope inclusion or CD27 agonism did not stimulate regulatory T cells, and vaccine efficacy was also improved by CD27 agonism in the presence of CD4(+) T-cell help. Our findings provide a preclinical rationale to apply CD27 agonist antibodies, either alone or combined with PD-1 blockade, to improve the therapeutic efficacy of cancer vaccines and immunotherapy generally. Cancer Res; 76(10); 2921-31. ©2016 AACR.
Highlights
Therapeutic vaccination with protein or DNA, aimed at raising a cytotoxic T lymphocyte (CTL) response to pre-existing cancer, is an attractive form of immunotherapy
dendritic cells (DC) are expert at cross-presenting antigens, i.e., loading peptides derived from the extracellular vaccine into MHC Class I molecules for presentation to CD8þ T cells
We demonstrate that antibody-based CD27 agonism is a very powerful combination to optimize therapeutic vaccination that acts synergistically with PD-1 blockade
Summary
Therapeutic vaccination with protein or DNA, aimed at raising a cytotoxic T lymphocyte (CTL) response to pre-existing cancer, is an attractive form of immunotherapy. It is easy to apply, potentially cheap, and can be designed to avoid autoimmune responses [1]. Therapeutic vaccines have not been very successful, not even against immunogenic virus-induced cancers [1, 2]. Dendritic cells (DC) are a key target for antigen delivery [3]. DCs are expert at cross-presenting antigens, i.e., loading peptides derived from the extracellular vaccine into MHC Class I molecules for presentation to CD8þ T cells. Activated DCs are optimal for T-cell priming, because they produce the relevant costimulatory molecules and cytokines.
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