PTPN2 phosphatase deletion in T cells promotes anti-tumour immunity and CAR T-cell efficacy in solid tumours

EMBO J. 2020 Jan 15;39(2):e103637. doi: 10.15252/embj.2019103637. Epub 2019 Dec 5.

Abstract

Although adoptive T-cell therapy has shown remarkable clinical efficacy in haematological malignancies, its success in combating solid tumours has been limited. Here, we report that PTPN2 deletion in T cells enhances cancer immunosurveillance and the efficacy of adoptively transferred tumour-specific T cells. T-cell-specific PTPN2 deficiency prevented tumours forming in aged mice heterozygous for the tumour suppressor p53. Adoptive transfer of PTPN2-deficient CD8+ T cells markedly repressed tumour formation in mice bearing mammary tumours. Moreover, PTPN2 deletion in T cells expressing a chimeric antigen receptor (CAR) specific for the oncoprotein HER-2 increased the activation of the Src family kinase LCK and cytokine-induced STAT-5 signalling, thereby enhancing both CAR T-cell activation and homing to CXCL9/10-expressing tumours to eradicate HER-2+ mammary tumours in vivo. Our findings define PTPN2 as a target for bolstering T-cell-mediated anti-tumour immunity and CAR T-cell therapy against solid tumours.

Keywords: CAR T cells; STAT-5 signalling; TCR signalling; adoptive T-cell therapy; protein tyrosine phosphatase N2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antigen Presentation / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • Female
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Lymphocyte Activation / immunology*
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Neoplasms / genetics
  • Neoplasms / immunology
  • Neoplasms / therapy*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / physiology*
  • Receptor, ErbB-2 / physiology*
  • Receptors, Antigen, T-Cell / immunology*
  • Signal Transduction

Substances

  • Receptors, Antigen, T-Cell
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2
  • Ptpn2 protein, mouse