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Author Notes:

Correspondence: Periasamy Selvaraj, Ph.D., Department of Pathology and Laboratory Medicine, Emory University School of Medicine 7309 Woodruff Memorial Research, Building 101, Woodruff Circle Atlanta, GA 30322; Phone: 404-727-5929; Fax: 404-727-5764, pselvar@emory.edu

Disclosures: PS currently holds shares in Metaclipse Therapeutics Corporation, an early startup company that is planning to use GPI-anchored molecules to develop cancer vaccines.

Subjects:

Research Funding:

This work was supported by NIH Funding: 1 R01 CA138993-01A1 to PS and 1 F31 CA165897-01 to ENB and 11SDG5710004 to RS from American Heart Association.

Keywords:

  • breast cancer
  • membrane anchored cytokines
  • antitumor immunity
  • tumor microenvironment

Expression of membrane anchored cytokines and B7-1 alters tumor microenvironment and induces protective antitumor immunity in a murine breast cancer model

Tools:

Journal Title:

Vaccine

Volume:

Volume 31, Number 20

Publisher:

, Pages 2449-2456

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Many studies have shown that the systemic administration of cytokines or vaccination with cytokine-secreting tumors augments an antitumor immune response that can result in eradication of tumors. However, these approaches are hampered by the risk of systemic toxicity induced by soluble cytokines. In this study, we have evaluated the efficacy of 4TO7, a highly tumorigenic murine mammary tumor cell line, expressing glycosyl phosphatidylinositol (GPI)-anchored form of cytokine molecules alone or in combination with the costimulatory molecule B7-1 as a model for potential cell or membrane-based breast cancer vaccines. We observed that the GPI-anchored cytokines expressed on the surface of tumor cells greatly reduced the overall tumorigenicity of the 4TO7 tumor cells following direct live cell challenge as evidenced by transient tumor growth and complete regression within 30 days post challenge. Tumors co-expressing B7-1 and GPI-IL-12 grew the least and for the shortest duration, suggesting that this combination of immunostimulatory molecules is most potent. Protective immune responses were also observed following secondary tumor challenge. Further, the 4TO7-B7-1/GPI-IL-2 and 4TO7-B7-1/GPI-IL-12 transfectants were capable of inducing regression of a wild-type tumor growing at a distant site in a concomitant tumor challenge model, suggesting the tumor immunity elicited by the transfectants can act systemically and inhibit the tumor growth at a distant site. Additionally, when used as irradiated whole cell vaccines, 4TO7-B7-1/GPI-IL-12 led to a significant inhibition in tumor growth of day 7 established tumors. Lastly, we observed a significant decrease in the prevalence of myeloid-derived suppressor cells and regulatory T-cells in the tumor microenvironment on day 7 post challenge with 4TO7-B7-1/GPI-IL-12 cells, which provides mechanistic insight into antitumor efficacy of the tumor-cell membrane expressed IL-12. These studies have implications in designing membrane-based therapeutic vaccines with GPI-anchored cytokines for breast cancer.

Copyright information:

© 2013 Elsevier Ltd. All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported License (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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