Reprogramming responsiveness to checkpoint blockade in dysfunctional CD8 T cells

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

Research output: Contribution to journalArticle

2 Citations (Scopus)

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

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T-Lymphocytes
Autoimmunity
Antigens
Neoplasms
Sirolimus
Vaccination
Genes

Keywords

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

Cite this

Reprogramming responsiveness to checkpoint blockade in dysfunctional CD8 T cells. / Nelson, Christine E; Mills, Lauren J; McCurtain, Jennifer L.; Thompson, Emily; Seelig, Davis; Bhela, Siddheshvar; Quarnstrom, Clare F.; Fife, Brian T; Vezys, Vaiva.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 7, 12.02.2019, p. 2640-2645.

Research output: Contribution to journalArticle

Nelson, Christine E ; Mills, Lauren J ; McCurtain, Jennifer L. ; Thompson, Emily ; Seelig, Davis ; Bhela, Siddheshvar ; Quarnstrom, Clare F. ; Fife, Brian T ; Vezys, Vaiva. / Reprogramming responsiveness to checkpoint blockade in dysfunctional CD8 T cells. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 7. pp. 2640-2645.
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