title: Development of tumor-infiltrating CD8+ T cell memory precursor effector cells and antimelanoma memory responses are the result of vaccination and TGF-β blockade during the perioperative period of tumor resection.
abstract: A main goal of cancer immunology research is the formation of Ag-specific memory T cell immunity capable of activation upon tumor re-encounter. The requirements necessary to overcome the inhibitory signals present in the tumor microenvironment and form such memory T cell responses are unknown. In contrast to previous studies targeting tumors expressing highly immunogenic model Ags, we demonstrate that alleviating tumor-induced suppression along with vaccination against authentic Ags during the perioperative period provides long-lasting protection against a highly suppressive and poorly immunogenic melanoma. In this study, we employed DNA vaccination with an immunologically optimized mouse melanoma-shared Ag, Trp1ee/ng, combined with systemic TGF-β blockade during the perioperative period of primary tumor resection, to confer protection against B16 melanoma, and against JBRH, an independently derived melanoma unrelated to B16. Importantly, we demonstrate that correlative to memory responses, perioperative immunotherapy increases the formation of tumor-infiltrating and tumor-reactive CD8(+) T cells expressing low levels of the transcription factor T-bet, defined as memory precursor effector cells. We show that conditions for an immunologically fertile environment are met when TGF-β blockade and vaccination are applied during the perioperative period of primary tumor resection. These findings address limitations of current CD8(+) T cell immunotherapies against cancer by generating effective CD8(+) T cell memory recall responses.
authors.affiliation: Committee on Immunology, Department of Surgery, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Emily C
authors.initials: EC
authors.lastname: Bellavance
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Kohlhapp
authors.forename: Andrew
authors.initials: A
authors.lastname: Zloza
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: O'Sullivan
authors.forename: James
authors.initials: J
authors.lastname: McCracken
authors.forename: Michael C
authors.initials: MC
authors.lastname: Jagoda
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Lacek
authors.forename: Mitchell C
authors.initials: MC
authors.lastname: Posner
authors.forename: Jose A
authors.initials: JA
authors.lastname: Guevara-Patino
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D018827:Carcinoma, Lewis Lung / Q000276:immunology / Q000473:pathology / Q000601:surgery; D004359:Drug Therapy, Combination; D007117:Immunization, Secondary / Q000379:methods; D007156:Immunologic Memory / Q000235:genetics; D016219:Immunotherapy, Adoptive / Q000379:methods; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology; D008297:Male; D008546:Melanoma, Experimental / Q000473:pathology / Q000601:surgery* / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010088:Oxidoreductases / Q000008:administration & dosage / Q000627:therapeutic use*; D059035:Perioperative Period / Q000379:methods; D013234:Stem Cells / Q000276:immunology / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000502:physiology; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use
chemical_list: D019496:Cancer Vaccines; D008562:Membrane Glycoproteins; D016212:Transforming Growth Factor beta; D019444:Vaccines, DNA; D010088:Oxidoreductases; C079621:Tyrp1 protein, mouse