Notch-mediated conversion of activated T cells into stem cell memory-like T cells for adoptive immunotherapy

Nat Commun. 2017 May 22;8:15338. doi: 10.1038/ncomms15338.

Abstract

Adoptive T-cell immunotherapy is a promising approach to cancer therapy. Stem cell memory T (TSCM) cells have been proposed as a class of long-lived and highly proliferative memory T cells. CD8+ TSCM cells can be generated in vitro from naive CD8+ T cells via Wnt signalling; however, methods do not yet exist for inducing TSCM cells from activated or memory T cells. Here, we show a strategy for generating TSCM-like cells in vitro (iTSCM cells) from activated CD4+ and CD8+ T cells in mice and humans by coculturing with stromal cells that express a Notch ligand. iTSCM cells lose PD-1 and CTLA-4 expression, and produce a large number of tumour-specific effector cells after restimulation. This method could therefore be used to generate antigen-specific effector T cells for adoptive immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / cytology
  • CTLA-4 Antigen / metabolism
  • Cell Differentiation
  • Cell Line
  • Cell Proliferation
  • Cell Separation
  • Coculture Techniques
  • Flow Cytometry
  • Homeostasis
  • Humans
  • Immunologic Memory
  • Immunotherapy, Adoptive / methods*
  • Ligands
  • Lymphocyte Activation*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Oligonucleotide Array Sequence Analysis
  • Programmed Cell Death 1 Receptor / metabolism
  • Receptors, Notch / metabolism*
  • Stem Cells / cytology
  • T-Lymphocytes / cytology*

Substances

  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Ligands
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Receptors, Notch