title: Deliberately provoking local inflammation drives tumors to become their own protective vaccine site.
abstract: Anti-cancer immunotherapies aim to generate resolution of all existing tumors, including inaccessible ones, and provide long-term protection against recurrence. This is rarely achieved. Thus, we aimed to determine if the tumor microenvironment could be turned into a potent 'self'-vaccine site. Our target was to eradicate larger tumor burdens. Our models respond to single-agent immunotherapies; however, they fail at a precisely defined 'cut-off' tumor burden. Thus, this system was used to define the immune mechanisms required to mediate regression of larger tumors that are resistant to mono-immunotherapies. We report that direct injection of IL-2 with agonist anti-CD40 antibody into the tumor bed resulted in permanent resolution of treated and untreated distal tumors. Tumor-infiltrating CD8(+) T cells and neutrophils collaborated to eradicate treated tumors, IFNgamma was not critical and protective memory was preserved. This approach relied only on tumor antigens expressed within the tumor microenvironment. It also avoided systemic toxicities, did not require chemotherapy or surgery and is clinically useful because only one tumor site has to be accessible for treatment. We conclude that provoking intra-tumoral inflammation skews the tumor microenvironment from tumorigenic to immunogenic, resulting in the resolution of treated and untreated distal tumors, as well long-term protective memory.
authors.affiliation: School of Biomedical Sciences, Curtin University, Kent St Bentley, Perth, Western Australia 6102, Australia.
authors.forename: Connie
authors.initials: C
authors.lastname: Jackaman
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lew
authors.forename: Yifan
authors.initials: Y
authors.lastname: Zhan
authors.forename: Jane E
authors.initials: JE
authors.lastname: Allan
authors.forename: Biljana
authors.initials: B
authors.lastname: Koloska
authors.forename: Peter T
authors.initials: PT
authors.lastname: Graham
authors.forename: Bruce W S
authors.initials: BW
authors.lastname: Robinson
authors.forename: Delia J
authors.initials: DJ
authors.lastname: Nelson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D001194:Asbestos / Q000009:adverse effects; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D019013:CD40 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D019496:Cancer Vaccines; D002460:Cell Line; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects; D007167:Immunotherapy; D007275:Injections, Intravenous; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000276:immunology; D008212:Lymphocyte Depletion; D008654:Mesothelioma / Q000276:immunology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000276:immunology / Q000628:therapy; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D019496:Cancer Vaccines; D007376:Interleukin-2; D011994:Recombinant Proteins; D001194:Asbestos