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Related Experiment Video

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Reprogramming responsiveness to checkpoint blockade in dysfunctional CD8 T cells.

Christine E Nelson1,2, Lauren J Mills3, Jennifer L McCurtain1

  • 1Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455.

Proceedings of the National Academy of Sciences of the United States of America
|January 26, 2019
PubMed
Summary
This summary is machine-generated.

Checkpoint blockade therapy effectiveness hinges on T cell activation status. Antigenic stimulation can reawaken tolerant T cells, enabling them to synergize with checkpoint blockade for tumor control without autoimmunity.

Keywords:
CD8 T cellscheckpointdysfunctiontolerancetumor

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Area of Science:

  • Immunology
  • Cancer Biology
  • T Cell Biology

Background:

  • T cell dysfunction hinders antitumor responses, and checkpoint blockade aims to reverse this.
  • Many patients do not respond to checkpoint blockade or experience autoimmune side effects.
  • The reasons for variable T cell responsiveness to checkpoint blockade are not fully understood.

Purpose of the Study:

  • To investigate the role of T cell activation status in response to checkpoint blockade.
  • To identify strategies for overcoming T cell tolerance and enhancing antitumor immunity.
  • To explore the potential of antigenic reeducation in combination with checkpoint blockade.

Main Methods:

  • Analysis of self-specific and tumor-specific CD8 T cell activation states and gene signatures.
  • Assessment of T cell responses to various checkpoint inhibitors (anti-CTLA4, anti-PD-L1, anti-PD-1, anti-LAG-3, anti-TIM-3).
  • Evaluation of T cell responsiveness after vaccination with cognate antigen and subsequent checkpoint blockade treatment.

Main Results:

  • Newly activated T cells respond to checkpoint blockade, causing autoimmunity mitigated by mTOR inhibition.
  • Tolerant T cells exhibit a dysfunctional gene signature and do not respond to checkpoint blockade.
  • Antigenic reeducation of tolerant T cells alters their transcriptional profile and induces responsiveness.
  • Antigenic reeducation combined with checkpoint blockade generates functional CD8 T cells that eliminate tumors without autoimmunity.

Conclusions:

  • T cell responsiveness to checkpoint blockade is critically dependent on their activation state.
  • Antigenic stimulation can overcome T cell tolerance and re-sensitize T cells to checkpoint blockade.
  • Combining antigenic reeducation with checkpoint blockade offers a promising strategy for enhancing antitumor immunity and managing autoimmunity.