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* Department of Surgery,
Julia McFarlane Diabetes Research Centre and Department of Microbiology and Infectious Diseases,
Department of Pathology, and
Department of Oncology, University of Calgary, Calgary, Alberta, Canada
Intact tolerogenic mechanisms preclude effective immunity against tumors, as most tumor Ags differ little from normal host Ags. In contrast, when tolerance fails, the immune system becomes inappropriately activated against an autoantigen. We postulated that CD8+ T cells activated during autoimmunity are capable of protecting against tumors that express the targeted autoantigen. To test this hypothesis, double-transgenic 8.3-NOD-RIPTAg mice were developed (where NOD is nonobese diabetic, RIP is rat insulin promoter, and TAg is large T Ag). In this model, individuals with the RIPTAg transgene develop insulinoma; those expressing a transgenic TCR (8.3-TCR) recognizing the islet-specific glucose 6 phosphatase catalytic subunit-related protein (IGRP) harbor a peripheral immune system dominated by diabetogenic CD8+ T cells. Although tumor emergence was significantly slower in 8.3-NOD-RIPTAg mice compared with NOD-RIPTAg mice, all 8.3-NOD-RIPTAg mice eventually developed insulinoma. Tumor emergence was not secondary to clonal deletion or anergy. Ag loss and MHC down-regulation were not apparent. Endogenous 8.3-TCR CD8+ T cells were recruited to the tumor site and proliferated upon arrival to the tumor, although they were notably absent from the central parts of more advanced tumors. These results demonstrate that a breakdown of tolerance capable of causing autoimmune disease is insufficient for effective tumor immunity. Alterations in the tumor microenvironment may inhibit efficient and comprehensive delivery of CD8+ T cells to all regions of the tumor. These data suggest that any immunotherapeutic strategy for cancer must involve enhancement of a proinflammatory tumor microenvironment in addition to inhibition of tolerogenic mechanisms.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This research was supported through grants from the Cancer Research Society and the American College of Surgeons. P. Serra was supported by a studentship from the Alberta Heritage Foundation for Medical Research (AHFMR). P. Santamaria was supported by the Canadian Diabetes Association and is a Scientist of the AHFMR.
2 K.Z. and C.C. contributed equally to this work.
3 Address correspondence and request reprints to Dr. Oliver F. Bathe, Tom Baker Cancer Centre, Division of Surgical Oncology, 1331 29th Street Northwest, Calgary, Alberta, T2N 4N1 Canada. E-mail address: oliverba{at}cancerboard.ab.ca
4 Abbreviations used in this paper: NOD, nonobese diabetic; DM, diabetes mellitus; IGRP, islet-specific glucose-6-phosphatase catalytic subunit-related protein; LN, lymph node; RIP, rat insulin promoter; TAg, large T antigen.
5 The online version of this article contains supplemental material.
This article has been cited by other articles:
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  D. E. H. Andersson and A. Sjoholm Comment on "Spontaneous Autoimmunity Sufficiently Potent to Induce Diabetes Mellitus Is Insufficient to Protect against Insulinoma" J. Immunol., September 15, 2009; 183(6): 3559 - 3560. [Full Text] [PDF]
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