Early Immunization Induces Persistent Tumor-Infiltrating CD8+ T Cells against an Immunodominant Epitope and Promotes Lifelong Control of Pancreatic Tumor Progression in SV40 Tumor Antigen Transgenic Mice

Abstract

The ability to recruit the host’s CD8+ T lymphocytes (TCD8) against cancer is often limited by the development of peripheral tolerance toward the dominant tumor-associated Ags. Because multiple epitopes derived from a given tumor Ag (T Ag) can be targeted by TCD8, vaccine approaches should be directed toward those TCD8 that are more likely to survive under conditions of persistent Ag expression. In this study, we investigated the effect of peripheral tolerance on the endogenous TCD8 response toward two epitopes, designated epitopes I and IV, from the SV40 large T Ag. Using rat insulin promoter (RIP) 1-Tag4 transgenic mice that express T Ag from the RIP and develop pancreatic insulinomas, we demonstrate that epitope IV- but not epitope I-specific TCD8 are maintained long term in tumor-bearing RIP1-Tag4 mice. Even large numbers of TCR-transgenic T cells specific for epitope I were rapidly eliminated from RIP1-Tag4 mice after adoptive transfer and recognition of the endogenous T Ag. Importantly, immunization of RIP1-Tag4 mice at 5 wk of age against epitope IV resulted in complete protection from tumor progression over a 2-year period despite continued expression of T Ag in the pancreas. This extensive control of tumor progression was associated with the persistence of functional epitope IV-specific TCD8 within the pancreas for the lifetime of the mice without the development of diabetes. This study indicates that an equilibrium is reached in which immune surveillance for spontaneous cancer can be achieved for the lifespan of the host while maintaining normal organ function.

Anti-CD40 Conditioning Enhances the TCD8 Response to a Highly Tolerogenic Epitope and Subsequent Immunotherapy of Simian Virus 40 T Antigen-Induced Pancreatic Tumors

“…A fourth epitope, designated epitope V, is immunorecessive and does not induce T CD8 unless the three dominant epitopes are inactivated (29). In previous studies using T Ag transgenic mice, we demonstrated that epitope Ispecific T CD8 are eliminated from the peripheral T cell repertoire more rapidly than T CD8 specific for epitope IV (8,9). In addition, immunization toward epitope IV can prevent the development of insulinomas in RT4 mice, although this approach fails to mediate the regression of established tumors (9).…”

“…In that study, however, the effect of such treatment on tumor progression was not investigated due to the slow onset of tumor appearance. Recently, we demonstrated that epitope I-specific T CD8 also are highly susceptible to peripheral tolerance in a different SV40 T Ag transgenic lineage, line RIP1-Tag4 (RT4) mice (9), which express SV40 T Ag as a transgene from the rat insulin promoter and develop insulinomas (24,25). T Ag expression begins around 5 wk of age in RT4 mice, leading to the development of islet hyperplasia by three months of age.…”

“…However, these T cells may be susceptible to the effects of peripheral tolerance following the recognition of tumor-associated self-Ags in vivo (5)(6)(7). The extent of T CD8 peripheral tolerance toward tumor-derived epitopes varies, with some epitopes inducing more rapid tolerance than others (8,9). To maximize the repertoire of potential tumor-reactive T cells, the effects of peripheral tolerance on T cells most susceptible to inactivation must be blocked.…”

In Vivo Imaging of an Inducible Oncogenic Tumor Antigen Visualizes Tumor Progression and Predicts CTL Tolerance

“…In most Tg models, Tag is expressed by a strong tissue-specific promoter, resulting in early CTL tolerance. However, in some Tag-Tg mice, including mice developing sporadic tumors in a stochastic fashion, functional epitope IV-specific CTLs were retained (10,(13)(14)(15)(16).…”

The immune response to sporadic colorectal cancer in a novel mouse model

“…The elimination of CFSE-labeled target cells in spleen of recipients was analyzed after 18 h by flow cytometry. in vivo kill was calculated: percentage of specific killing ¼ (1-(ratio of control mice/ratio of immunized mice) Â 100), where the ratio is the percentage of CFSE low /CFSE high (Otahal et al, 2006).…”