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 journalArticlepeer-review

9 Scopus citations

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

Bibliographical note

Funding Information:
We would like to thank Drs. Victor Engelhard, Thomas Griffith, Zong Sheng Guo, Ann Hill, Marc Jenkins, Nicholas Restifo, and Kimberly Schluns for reagents. This work was supported by NIH grant DP2OD006472 (to V.V.), a grant from the Randy Shaver Cancer Research and Community Fund (to V.V.), and NIH grant T32AI007313 (to C.E.N. and E.A.T.). Conceptualization, C.E.N. and V.V.; Methodology, C.E.N. E.A.T. C.F.Q. B.J.B. D.M. and V.V.; Validation, C.E.N. E.A.T. C.F.Q. and S.B.; Formal Analysis, C.E.N. E.A.T. C.F.Q. D.M.S. and S.B.; Investigation, C.E.N. E.A.T. C.F.Q. D.M.S. S.B. and K.A.F.; Resources, D.M. and V.V.; Writing ? Original Draft, C.E.N. and V.V.; Writing ? Review & Editing, C.E.N. E.A.T. C.F.Q. K.A.F. B.J.B. and V.V.; Visualization, C.E.N. E.A.T. C.F.Q. D.M.S. and S.B.; Supervision & Project Administration, V.V.; Funding Acquisition, C.E.N. E.A.T. and V.V. The authors declare no competing interests.

Funding Information:
We would like to thank Drs. Victor Engelhard, Thomas Griffith, Zong Sheng Guo, Ann Hill, Marc Jenkins, Nicholas Restifo, and Kimberly Schluns for reagents. This work was supported by NIH grant DP2OD006472 (to V.V.), a grant from the Randy Shaver Cancer Research and Community Fund (to V.V.), and NIH grant T32AI007313 (to C.E.N. and E.A.T.).

Publisher Copyright:
© 2019 The Author(s)

Keywords

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

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