CD4+ T-cell help in therapeutic cancer vaccination

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). Since 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 HPV-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 co-stimulation. 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 also 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 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.

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