Spontaneous autoimmunity sufficiently potent to induce diabetes mellitus is insufficient to protect against insulinoma.
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.
Zwicker
Kelley
K
Department of Surgery, University of Calgary, Calgary, Alberta, Canada.
Chatten
Christa
C
Gratton
Kathy
K
Demetrick
Doug
D
Serra
Pau
P
Shameli
Afshin
A
Santamaria
Pere
P
Bathe
Oliver F
OF
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003920:Diabetes Mellitus / Q000276:immunology; D007108:Immune Tolerance; D007340:Insulinoma / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology
D000951:Antigens, Neoplasm; D001324:Autoantigens