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International Immunology Advance Access originally published online on September 29, 2008
International Immunology 2008 20(11):1467-1479; doi:10.1093/intimm/dxn104
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© The Japanese Society for Immunology. 2008. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Deliberately provoking local inflammation drives tumors to become their own protective vaccine site

Connie Jackaman1, Andrew M. Lew2, Yifan Zhan2, Jane E. Allan1, Biljana Koloska3, Peter T. Graham3, Bruce W. S. Robinson1 and Delia J. Nelson1,3

1 School of Biomedical Sciences, Curtin University, Kent St Bentley, Perth, Western Australia 6102, Australia
2 School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia 6009, Australia
3 Walter and Eliza Hall Institute, Melbourne, Victoria 3050, Australia

Correspondence to: D. Nelson; E-mail: delianelson{at}curtin.edu.au

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, IFN{gamma} 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.

Keywords: agonist anti-CD40 antibody, anti-tumor immunity, IL-2, T cells, neutrophils

Transmitting editor: A. Kelso

Received 20 June 2008, accepted 26 August 2008.


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