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

Florian Wiede, Kun-Hui Lu, Xin Du, Shuwei Liang, Katharina Hochheiser, Garron T Dodd, Pei K Goh, Conor Kearney, Deborah Meyran, Paul A. Beavis, Melissa A. Henderson, Simone L. Park, Jason Waithman, Sheng Zhang, Zhong Yin Zhang, Jane Oliaro, Thomas Gebhardt, Phillip K Darcy, Tony Tiganis

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9 Citations (Scopus)

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.

Original languageEnglish
Article numbere103637
Number of pages26
JournalThe EMBO Journal
Volume39
Issue number2
DOIs
Publication statusPublished - 15 Jan 2020

Keywords

  • adoptive T-cell therapy
  • CAR T cells
  • protein tyrosine phosphatase N2
  • STAT-5 signalling
  • TCR signalling

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