Resistance to TGFβ suppression and improved anti-tumor responses in CD8 + T cells lacking PTPN22

Nat Commun. 2017 Nov 7;8(1):1343. doi: 10.1038/s41467-017-01427-1.

Abstract

Transforming growth factor β (TGFβ) is important in maintaining self-tolerance and inhibits T cell reactivity. We show that CD8+ T cells that lack the tyrosine phosphatase Ptpn22, a major predisposing gene for autoimmune disease, are resistant to the suppressive effects of TGFβ. Resistance to TGFβ suppression, while disadvantageous in autoimmunity, helps Ptpn22 -/- T cells to be intrinsically superior at clearing established tumors that secrete TGFβ. Mechanistically, loss of Ptpn22 increases the capacity of T cells to produce IL-2, which overcomes TGFβ-mediated suppression. These data suggest that a viable strategy to improve anti-tumor adoptive cell therapy may be to engineer tumor-restricted T cells with mutations identified as risk factors for autoimmunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmunity / immunology
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / transplantation
  • Female
  • Homeodomain Proteins / genetics
  • Immunotherapy, Adoptive / methods*
  • Interleukin-2 / metabolism
  • Male
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Ovalbumin / pharmacology
  • Ovarian Neoplasms / pathology
  • Ovarian Neoplasms / therapy
  • Peptide Fragments / pharmacology
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22 / genetics*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22 / metabolism
  • Receptors, Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / pharmacology*

Substances

  • Homeodomain Proteins
  • Interleukin-2
  • OVA-8
  • Peptide Fragments
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • RAG-1 protein
  • Ovalbumin
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22
  • Ptpn22 protein, mouse