The Fate of Low Affinity Tumor-Specific CD8+ T Cells in Tumor-Bearing Mice

Abstract

A major challenge in tumor immunology is how best to activate the relatively low avidity self-specific and tumor-specific T cells that are available in the self-tolerant repertoire. To address this issue, we produced a TCR transgenic mouse expressing a class I-restricted hemagglutinin (HA)-specific TCR (clone 1 TCR) derived from a mouse that expressed HA as a self-Ag in the insulin-producing β cells of the pancreatic islets (InsHA) mice. Upon transfer of clone 1 TCR CD8+ T cells into InsHA mice, very few cells were activated by cross-presented HA, indicating that the cells were retained in InsHA mice because they ignored the presence of Ag, and not because they were functionally inactivated by anergy or tuning. Upon transfer into recipient mice in which HA is expressed at high concentrations as a tumor-associated Ag in spontaneously arising insulinomas (RIP-Tag2-HA mice), a high proportion of clone 1 cells were activated when they encountered cross-presented tumor Ag in the pancreatic lymph nodes. However, the activated cells exhibited very weak effector function and were soon tolerized. The few activated cells that did migrate to the tumor were unable to delay tumor progression. However, when HA-specific CD4 helper cells were cotransferred with clone 1 cells into RIP-Tag2-HA recipients and the mice were vaccinated with influenza, clone 1 cells were found to exert a significant level of effector function and could delay tumor growth. This tumor model should prove of great value in identifying protocols that can optimize the function of low avidity tumor-specific T cells.

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

“…It remains possible that prolonged exposure to endogenous Tag renders TCR-V cells destined for future deletion because these cells are not retained at detectable levels unless the mice are immunized. Similar observations have been made with TCR-transgenic T cells responding to immunodominant tumor epitopes upon transfer into tumor-bearing mice (34,47,57). Our findings here using TCR-transgenic T cells imply that higher avidity endogenous epitope V specific T CD8 that survive negative selection in SV11 mice might additionally be subject to tolerance upon recognition of and activation by persistent Tag in the peripheral tissues, thereby contributing to the low levels of functional epitope V-specific T cells available for recruitment in tumor-bearing mice (17).…”

“…These studies were primarily performed using transplantable tumors that expressed foreign Ag. By contrast, it has been reported that under tolerizing conditions, immunodominant self-epitope specific T CD8 do not readily penetrate transplanted tumors that express self-Ag (34,47). Our results show that in the context of self-Ag expression, functionally competent Tag-V-specific T cells accumulate within the tumor, indicative of specific recognition of this epitope in vivo.…”

“…Vaccination approaches that target endogenous self/tumor-reactive T CD8 have met with varying levels of success in a number of tumor models (34,(42)(43)(44)(45)(46)(47)(48)(49). Unfortunately, such self-reactive cells are often subject to peripheral tolerance, limiting their effectiveness against progressing tumors.…”

Fusion to Listeriolysin O and Delivery by Listeria monocytogenes Enhances the Immunogenicity of HER-2/neu and Reveals Subdominant Epitopes in the FVB/N Mouse

“…The most effective antitumor response will likely be generated by enhancing low-affinity anti-HER-2/neu-specific CD8 ϩ T cells that were not deleted during thymic selection (46). This will be particularly important in transgenic mouse models of cancer in which the mice are tolerant to the tumor Ag and the high-affinity T cells that can be generated to target the tumor in wild-type (nontolerant) mice will not be present (47,48).…”

Adjuvants targeting innate and adaptive immunity synergize to enhance tumor immunotherapy

“…Clone 1 (CL1) CD8 T cells are also HA specific, but the T cell receptor (TCR) expressed by these cells was originally isolated from a mouse expressing HA in the pancreas and exhibits low affinity for HA (3). It would be expected that such low-avidity CD8 cells would more closely reflect what is available for tumor eradication in the endogenous repertoire.…”