Robust Iterative Stimulation with Self-Antigens Overcomes CD8+ T Cell Tolerance to Self- and Tumor Antigens

Christine E. Nelson, Emily A. Thompson, Clare F. Quarnstrom, Kathryn A. Fraser, Davis M. Seelig, Siddheshvar Bhela, Brandon J. Burbach, David Masopust, Vaiva Vezys

Research output: Contribution to journalArticle

Abstract

The immune system adapts to constitutive antigens to preserve self-tolerance, which is a major barrier for anti-tumor immunity. Antigen-specific reversal of tolerance constitutes a major goal to spur therapeutic applications. Here, we show that robust, iterative, systemic stimulation targeting tissue-specific antigens in the context of acute infections reverses established CD8+ T cell tolerance to self, including in T cells that survive negative selection. This strategy results in large numbers of circulating and resident memory self-specific CD8+ T cells that are widely distributed and can be co-opted to control established malignancies bearing self-antigen without concomitant autoimmunity. Targeted expansion of both self- and tumor neoantigen-specific T cells acts synergistically to boost anti-tumor immunity and elicits protection against aggressive melanoma. Our findings demonstrate that T cell tolerance can be re-adapted to responsiveness through robust antigenic exposure, generating self-specific CD8+ T cells that can be used for cancer treatment.

Original languageEnglish (US)
Pages (from-to)3092-3104.e5
JournalCell reports
Volume28
Issue number12
DOIs
StatePublished - Sep 17 2019

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T-cells
Autoantigens
Neoplasm Antigens
T-Lymphocytes
Tumors
Neoplasms
Antigens
Immunity
Bearings (structural)
Self Tolerance
Oncology
Immune system
Autoimmunity
Immune System
Melanoma
Tissue
Data storage equipment
Therapeutics
Infection

Keywords

  • CD8 T cell
  • cancer
  • dysfunction
  • exhaustion
  • neo-antigen
  • resident memory
  • reversal
  • self-antigen
  • tolerance
  • vaccination

PubMed: MeSH publication types

  • Journal Article

Cite this

Robust Iterative Stimulation with Self-Antigens Overcomes CD8+ T Cell Tolerance to Self- and Tumor Antigens. / Nelson, Christine E.; Thompson, Emily A.; Quarnstrom, Clare F.; Fraser, Kathryn A.; Seelig, Davis M.; Bhela, Siddheshvar; Burbach, Brandon J.; Masopust, David; Vezys, Vaiva.

In: Cell reports, Vol. 28, No. 12, 17.09.2019, p. 3092-3104.e5.

Research output: Contribution to journalArticle

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