Antitumor immunity can be uncoupled from autoimmunity following heat shock protein 70-mediated inflammatory killing of normal pancreas

Timothy Kottke, Jose S Pulido, Jill Thompson, Luis Sanchez-Perez, Heung Chong, Stuart K. Calderwood, Peter Selby, Kevin Harrington, Scott E. Strome, Alan Melcher, Richard Geoffrey Vile

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24 Scopus citations

Abstract

We have a long-term interest in the connectivity between autoimmunity and tumor rejection. However, outside of the melanocyte/melanoma paradigm, little is known about whether autoimmune responses to normal tissue can induce rejection of tumors of the same histologic type. Here, we induced direct, pathogen-like cytotoxicity to the normal pancreas in association with the immune adjuvant heat shock protein 70. In sharp contrast to our studies with a similar approach for the treatment of prostate cancer, inflammatory killing of the normal pancreas induced a Th1-like, anti-self-response to pancreatic antigens, which was rapidly suppressed by a concomitant suppressive regulatory T cell (Treg) response. Interestingly, even when Treg cells were depleted, the Th1-like response was insufficient to induce significant ongoing autoimmunity. However, the Th1-like response to antigens expressed in the pancreas at the time of damage was sufficient to induce rejection of tumors expressing either a foreign (ova) antigen or fully syngeneic tumor antigens (on Panc02 tumor cells), provided that Treg were depleted before inflammatory killing of the normal pancreas. Taken together, these data indicate that profound differences exist between the immunoprotective mechanisms in place between different tissues (pancreas and prostate) in their response to pathogen-like damage. Moreover, they also show that, although multiple layers of immunologic safeguards are in place to prevent the development of severe autoimmune consequences in the pancreas (in contrast to the prostate), tumor rejection responses can still be decoupled from pathologic autoimmune responses in vivo, which may provide novel insights into the immunotherapeutic treatment of pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)7767-7774
Number of pages8
JournalCancer Research
Volume69
Issue number19
DOIs
StatePublished - Oct 1 2009

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Kottke, T., Pulido, J. S., Thompson, J., Sanchez-Perez, L., Chong, H., Calderwood, S. K., Selby, P., Harrington, K., Strome, S. E., Melcher, A., & Vile, R. G. (2009). Antitumor immunity can be uncoupled from autoimmunity following heat shock protein 70-mediated inflammatory killing of normal pancreas. Cancer Research, 69(19), 7767-7774. https://doi.org/10.1158/0008-5472.CAN-09-1597