title: Booster vaccinations against cancer are critical in prophylactic but detrimental in therapeutic settings.
abstract: Although cancer vaccines are in the clinic, several issues remain to be addressed to increase vaccine efficacy. In particular, whether how and how frequently a patient should be boosted remains to be defined. Here, we have assessed the ability of dendritic cell (DC)-based vaccines to induce a long-lasting tumor-specific CTL response in either prophylactic or therapeutic settings by taking advantage of transplantable and spontaneous mouse tumor models. Implementing a 24-hour ex vivo intracellular cytokine production assay, we have found that priming with a DC-based vaccine induced a long-lasting CTL response in wild-type mice, and homologous boosting better sustained the pool of central memory T cells, which associated with potent protection against B16F1 melanoma challenge. Appropriate timing of booster vaccination was also critical, as a tight boosting schedule hindered persistence of IFN-γ-competent memory CD8(+) T cells and mice survival in prophylactic settings. Conversely, prime/boost vaccination proved to be of no advantage or even detrimental in therapeutic settings in B16F1 and transgenic adenocarcinoma of the mouse prostate (TRAMP) models, respectively. Although DC priming was indeed needed for tumor shrinkage, restoration of immune competence, and prolonged survival of TRAMP mice, repeated boosting did not sustain the pool of central memory CTLs and was detrimental for mice overall survival. Thus, our results indicate that booster vaccinations impact antitumor immunity to different extents, depending on their prophylactic or therapeutic administration, and suggest evaluating the need for boosting in any given patient with cancer depending on the state of the disease.
authors.affiliation: Cellular Immunology Unit; Program of Immunology, Gene Therapy and Bio-Immunotherapy of Cancer (PIBIC, Milan, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Ricupito
authors.forename: Matteo
authors.initials: M
authors.lastname: Grioni
authors.forename: Arianna
authors.initials: A
authors.lastname: Calcinotto
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Hess Michelini
authors.forename: Renato
authors.initials: R
authors.lastname: Longhi
authors.forename: Anna
authors.initials: A
authors.lastname: Mondino
authors.forename: Matteo
authors.initials: M
authors.lastname: Bellone
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D005434:Flow Cytometry; D018380:Hematopoietic Stem Cell Transplantation; D007117:Immunization, Secondary / Q000379:methods*; D007156:Immunologic Memory / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: D019496:Cancer Vaccines; D016207:Cytokines; D007371:Interferon-gamma