Control of Advanced Choroid Plexus Tumors in SV40 T Antigen Transgenic Mice Following Priming of Donor CD8+ T Lymphocytes by the Endogenous Tumor Antigen

The Journal of Immunology

2006

Self Cite

Self-reactive T cells that survive the process of positive and negative selection during thymocyte development represent potential effector cells against tumors that express these same self-Ags. We have previously shown that CD8+ T lymphocytes (TCD8) specific for an immunorecessive epitope, designated epitope V, from the SV40 large T Ag (Tag) escape thymic deletion in line SV11 Tag-transgenic mice. In contrast, these mice are tolerant to the three most dominant Tag epitopes. The majority of the residual epitope V-specific TCD8 have a low avidity for the target epitope, but a prime/boost regimen can expand higher avidity clones in vivo. Whether higher avidity TCD8 targeting this epitope are affected by Tag-expressing tumors in the periphery or can be recruited for control of tumor progression remains unknown. In the current study, we determined the fate of naive TCR-transgenic TCD8 specific for Tag epitope V (TCR-V cells) following transfer into SV11 mice bearing advanced-stage choroid plexus tumors. The results indicate that TCR-V cells are rapidly triggered by the endogenous Tag and acquire effector function, but fail to accumulate within the tumors. Primary immunization enhanced TCR-V cell frequency in the periphery and promoted entry into the brain, but a subsequent booster immunization caused a dramatic accumulation of TCR-V T cells within the tumors and inhibited tumor progression. These results indicate that epitope V provides a target for CD8+ T cells against spontaneous tumors in vivo, and suggests that epitopes with similar properties can be harnessed for tumor immunotherapy.

Section: Discussionmentioning

confidence: 48%

Section: Tag Epitope V-targeted Immunization Promotes Tcr-v Cell Entrmentioning

confidence: 99%

“…Spleens and LN were processed to single-cell suspensions and spleens were depleted of RBCs using Tris NH 4 Cl. Lymphocytes were isolated from brains as described previously (31).…”

Section: Lymphocyte Isolationmentioning

confidence: 99%

Section: Intracellular Cytokine Assaymentioning

confidence: 99%

See 2 more Smart Citations

Accumulation of CD8+ T Cells in Advanced-Stage Tumors and Delay of Disease Progression following Secondary Immunization against an Immunorecessive Epitope

Ryan

The Journal of Immunology

2006

Self Cite

“…Epitope V is immunorecessive and not immunogenic unless the three dominant epitopes are inactivated in T Ag (29,30). The ability of T CD8 -specific for T Ag to control tumor progression was established by showing that the transfer of T CD8 specific for the immunodominant T Ag epitopes into SV11 T Ag transgenic mice induced regression of advanced stage spontaneous tumors (31).…”

mentioning

confidence: 99%

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

Otáhal

The Journal of Immunology

Hutchinson

et al. 2006

Self Cite

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.

Rapid accumulation of adoptively transferred CD8+ T cells at the tumor site is associated with long-term control of SV40 T antigen-induced tumors

Yorty

Tevethia

Cancer Immunol Immunother

2007

Self Cite

We previously established a model to study CD8(+) T cell (T(CD8))-based adoptive immunotherapy of cancer using line SV11 mice that develop choroid plexus tumors in the brain due to transgenic expression of Simian Virus 40 large T antigen (Tag). These mice are tolerant to the three dominant T(CD8)-recognized Tag epitopes I, II/III and IV. However, adoptive transfer of spleen cells from naïve C57BL/6 (B6) mice prolongs SV11 survival following T(CD8) priming against the endogenous Tag epitope IV. In addition, survival of SV11 mice is dramatically increased following transfer of lymphocytes from Tag-immune B6 mice. In the current study, we compared the kinetics and magnitude of Tag-specific T(CD8) accumulation at the tumor site following adoptive transfer with a high dose of either Tag-immune or naïve donor cells or decreasing doses of Tag-immune lymphocytes. Following adoptive transfer of Tag-immune cells, epitope I- and IV-specific T(CD8) accumulated to high levels in the brain of SV11 mice, peaking at 5-7 days, while epitope IV-specific T(CD8 )derived from naïve donors required three weeks to achieve peak levels. A similar delay in the peak of epitope IV-specific T(CD8) accumulation was observed when tenfold fewer Tag-immune donor cells were administered, reducing control of tumor progression. These results suggest that efficient and prolonged control of established autochthonous tumors is associated with high-level early accumulation of adoptively transferred T cells. We also provide evidence that although multiple specificities are represented in the Tag immune donor lymphocytes, epitope IV-specific donor T(CD8) play a predominant role in control of tumor growth.