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Cells of the Adaptive Immune Response01:23

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The T and B lymphocytes of the adaptive immune system develop from common lymphoid progenitor cells in the bone marrow. These progenitors give rise to precursors that eventually develop into both T and B lymphocytes. As these precursors mature, they gain the ability to detect and respond to foreign antigens in the body, a process known as immunocompetence. Additionally, these precursors acquire self-tolerance, a process that ensures they do not react to self-antigens. This intricate system...
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An engineered IL-2 partial agonist promotes CD8+ T cell stemness.

Fei Mo1, Zhiya Yu2, Peng Li1

  • 1Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.

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|September 16, 2021
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Summary

An engineered cytokine, H9T, expands CD8+ T cells for cancer immunotherapy without causing terminal differentiation. This approach maintains a stem-cell-like state, enhancing anti-tumor activity in preclinical models.

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Area of Science:

  • Immunology
  • Molecular Biology
  • Biotechnology

Background:

  • Adoptive T cell transfer is a key cancer immunotherapy strategy.
  • T cell number and differentiation state critically impact therapeutic efficacy.
  • Standard T cell expansion methods can lead to terminal differentiation and reduced efficacy.

Purpose of the Study:

  • To investigate the effects of H9T, an engineered interleukin-2 partial agonist, on CD8+ T cell expansion and differentiation.
  • To determine if H9T can maintain a stem-cell-like state in T cells for improved immunotherapy.
  • To evaluate the therapeutic potential of H9T-expanded T cells in preclinical cancer models.

Main Methods:

  • Utilized H9T, an engineered interleukin-2 partial agonist, for T cell expansion.
  • Analyzed STAT5 signaling, transcriptional, epigenetic, and metabolic changes.
  • Assessed T cell transcription factor 1 (TCF-1) expression and mitochondrial fitness.
  • Evaluated anti-tumor activity of H9T-expanded T cells in mouse models.

Main Results:

  • H9T promoted CD8+ T cell expansion without driving terminal differentiation.
  • Distinct downstream transcriptional, epigenetic, and metabolic programs were observed.
  • H9T sustained TCF-1 expression and promoted mitochondrial fitness, maintaining a stem-cell-like state.
  • H9T-expanded TCR-transgenic and CAR-modified T cells demonstrated robust anti-tumor activity in vivo.

Conclusions:

  • Engineered cytokine variants like H9T offer a promising strategy for enhancing T cell-based cancer immunotherapies.
  • H9T facilitates the expansion of functional, stem-cell-like CD8+ T cells.
  • This approach holds translational potential for developing novel immunotherapeutic agents.