title: CD27 Agonism Plus PD-1 Blockade Recapitulates CD4+ T-cell Help in Therapeutic Anticancer Vaccination.
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.
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, the Netherlands.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Ahrends
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, the Netherlands.
authors.forename: Nikolina
authors.initials: N
authors.lastname: Bąbała
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, the Netherlands.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.affiliation: Aduro Biotech Europe, Oss, the Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: van Eenennaam
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, the Netherlands. j.borst@nki.nl.
authors.forename: Jannie
authors.initials: J
authors.lastname: Borst
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen / Q000276:immunology; D019496:Cancer Vaccines / Q000627:therapeutic use*; D049109:Cell Proliferation; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014407:Tumor Cells, Cultured; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000819:agonists*; D014611:Vaccination
chemical_list: D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7