Pancreatic cancer regression by intratumoral injection of live Streptococcus pyogenes in a syngeneic mouse model

Claudia Maletzki ^1*, Michael Linnebacher ², Bernd Kreikemeyer ³ and Joerg Emmrich ¹

¹ Division of Gastroenterology, Department of Internal Medicine, University of Rostock, Germany
² Department of General-, Thoracic-, Vascular- and Transplantation Surgery, University of Rostock, Germany
³ Department of Medical Microbiology and Hospital Hygiene, University of Rostock, Germany

^* To whom correspondence should be addressed. E-mail: claudia.maletzki{at}uni-rostock.de.

Accepted 6 November 2007

Abstract

Background: This study addressed the potential of bacteriolytic therapy using Streptococcus pyogenes in a syngeneic pancreatic carcinoma mouse model. Methods: Panc02 tumors were either infected with S. pyogenes or were treated with the equivalent volume of vehicle. In addition to assessment of tumor histology and immunohistochemistry, isolated splenocytes were analyzed by flow cytometry. IFN- secretion as reaction of splenocytes against tumor cells was shown through ELISpot technique. A cytotoxic effect of lymphocytes against tumor targets was detected by LDH release. Cytokine levels in serum were measured. Results: A single application of live bacteria into established Panc02 tumors resulted in complete tumor regression. This antitumoral effect was accompanied by massive leukocyte infiltration into the tumors as well as a significant and sustained elevation of systemic levels of the proinflammatory cytokines IFN-, TNF-and IL-6. Lymphocytes obtained from treated mice specifically recognized syngeneic tumor cells in IFN--ELISpot and most importantly in cellular cytotoxicity assays indicating a tumor-specific immune response. Conclusions: We provide data that both the direct lytic activity of S. pyogenes towards tumor cells and the infection-driven infiltration of tumors by cells of the innate immune system lead to a damage of tumor cells followed by a dissemination of tumor components. This last outcome allows for the activation of tumor-specific effector cells, most likely in draining lymph nodes, promoted by the proinflammatory context. Taken together, these data indicate that the application of live S. pyogenes may be a promising new treatment strategy for advanced pancreatic cancer patients that warrants further investigation.

Keywords: bacteriolytic therapy, immune response, mouse model, pancreatic cancer

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