Reprogramming responsiveness to checkpoint blockade in dysfunctional CD8 T cells

Christine E. Nelson, Lauren J. Mills, Jennifer L. McCurtain, Emily A. Thompson, Davis M. Seelig, Siddheshvar Bhela, Clare F. Quarnstrom, Brian T. Fife, Vaiva Vezys

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Established T cell dysfunction is a barrier to antitumor responses, and checkpoint blockade presumably reverses this. Many patients fail to respond to treatment and/or develop autoimmune adverse events. The underlying reason for T cell responsiveness remains elusive. Here, we show that susceptibility to checkpoint blockade is dependent on the activation status of T cells. Newly activated self-specific CD8 T cells respond to checkpoint blockade and cause autoimmunity, which is mitigated by inhibiting the mechanistic target of rapamycin. However, once tolerance is established, self-specific CD8 T cells display a gene signature comparable to tumor-specific CD8 T cells in a fixed state of dysfunction. Tolerant self-specific CD8 T cells do not respond to single or combinatorial dosing of anti-CTLA4, anti–PD-L1, anti–PD-1, anti–LAG-3, and/or anti–TIM-3. Despite this, T cell responsiveness can be induced by vaccination with cognate antigen, which alters the previously fixed transcriptional signature and increases antigen-sensing machinery. Antigenic reeducation of tolerant T cells synergizes with checkpoint blockade to generate functional CD8 T cells, which eliminate tumors without concomitant autoimmunity and are transcriptionally distinct from classic effector T cells. These data demonstrate that responses to checkpoint blockade are dependent on the activation state of a T cell and show that checkpoint blockade-insensitive CD8 T cells can be induced to respond to checkpoint blockade with robust antigenic stimulation to participate in tumor control.

Original languageEnglish (US)
Pages (from-to)2640-2645
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number7
DOIs
StatePublished - Feb 12 2019

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. We thank Rachel Davis for expert technical assistance. This work was supported by the NIH Grant DP2OD006472 (to V.V.), the Randy Shaver Cancer Research Fund (V.V.), and the NIH Grant T32AI007313 (to C.E.N. and E.A.T.).

Publisher Copyright:
© 2019 National Academy of Sciences. All Rights Reserved.

Keywords

  • CD8 T cells
  • Checkpoint
  • Dysfunction
  • Tolerance
  • Tumor

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