Apoptosis-regulated low-avidity cancer-specific CD8(+) T cells can be rescued to eliminate HER2/neu-expressing tumors by costimulatory agonists in tolerized mice

Research output: Contribution to journalArticle

Abstract

A major barrier to vaccines in cancer treatment is their failure to activate and maintain a complete cancer-specific CD8(+) effector T-cell repertoire. Low-avidity T cells are more likely to escape clonal deletion in the thymus when compared with high-avidity T cells, and therefore comprise the major population of effector T cells available for activation in patients with cancer. However, low-avidity T cells fail to traffic into the tumor microenvironment and function in eradicating tumor under optimal vaccination conditions as opposed to high-avidity T cells that escape clonal deletion and function in tumor killing. We used high- and low-avidity T-cell receptor transgenic CD8(+) T cells specific for the immunodominant epitope HER2/neu (RNEU420-429) to identify signaling pathways responsible for the inferior activity of the low-avidity T cells. Adoptive transfer of these cells into tumor-bearing vaccinated mice identified the members of apoptosis pathways that are upregulated in low-avidity T cells. The increased expression of proapoptotic proteins by low-avidity T cells promoted their own cell death and also that of other tumor-specific CD8(+) T cells within their local environment. Importantly, we show that this proapoptotic effect can be overcome by using a strong costimulatory signal that prevents the activation-induced cell death and enables the low-avidity T cells to traffic into the tumor and assist in tumor clearance. These findings identify new therapeutic opportunities for activating the most potent anticancer T-cell responses.

Original languageEnglish (US)
Pages (from-to)307-319
Number of pages13
JournalCancer immunology research
Volume2
Issue number4
DOIs
StatePublished - Apr 1 2014

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Apoptosis
T-Lymphocytes
Neoplasms
Clonal Deletion
Cell Death
Immunodominant Epitopes
Cancer Vaccines
Tumor Microenvironment
Adoptive Transfer
T-Cell Antigen Receptor
Thymus Gland
Vaccination
Therapeutics
Population

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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title = "Apoptosis-regulated low-avidity cancer-specific CD8(+) T cells can be rescued to eliminate HER2/neu-expressing tumors by costimulatory agonists in tolerized mice",
abstract = "A major barrier to vaccines in cancer treatment is their failure to activate and maintain a complete cancer-specific CD8(+) effector T-cell repertoire. Low-avidity T cells are more likely to escape clonal deletion in the thymus when compared with high-avidity T cells, and therefore comprise the major population of effector T cells available for activation in patients with cancer. However, low-avidity T cells fail to traffic into the tumor microenvironment and function in eradicating tumor under optimal vaccination conditions as opposed to high-avidity T cells that escape clonal deletion and function in tumor killing. We used high- and low-avidity T-cell receptor transgenic CD8(+) T cells specific for the immunodominant epitope HER2/neu (RNEU420-429) to identify signaling pathways responsible for the inferior activity of the low-avidity T cells. Adoptive transfer of these cells into tumor-bearing vaccinated mice identified the members of apoptosis pathways that are upregulated in low-avidity T cells. The increased expression of proapoptotic proteins by low-avidity T cells promoted their own cell death and also that of other tumor-specific CD8(+) T cells within their local environment. Importantly, we show that this proapoptotic effect can be overcome by using a strong costimulatory signal that prevents the activation-induced cell death and enables the low-avidity T cells to traffic into the tumor and assist in tumor clearance. These findings identify new therapeutic opportunities for activating the most potent anticancer T-cell responses.",
author = "Black, {Chelsea M.} and Armstrong, {Todd D} and Elizabeth Jaffee",
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