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

• Florian Wiede ^[4] ; Kun‐Hui Lu ^[5] ; Xin Du ^[6] ; Shuwei Liang ^[4] ; Katharina Hochheiser ^[7] ; Garron T Dodd ^[8] ; Pei K Goh ^[4] ; Conor Kearney ^[5] ; Deborah Meyran ^[5] ; Paul A Beavis ^[6] ; Melissa A Henderson ^[5] ; Simone L Park ^[1] ; Jason Waithman ^[2] ; Sheng Zhang ^[3] ; Zhong‐Yin Zhang ^[3] ; Jane Oliaro ^[6] ; Thomas Gebhardt ^[1] ; Phillip K Darcy ^[6] ; Tony Tiganis ^[4]
  1. [1] University of Melbourne

     University of Melbourne

     Australia

     
  2. [2] University of Western Australia

     University of Western Australia

     Australia

     
  3. [3] Purdue University

     Purdue University

     Township of Wabash, Estados Unidos

     
  4. [4] 1 Monash Biomedicine Discovery Institute Monash University Clayton Vic. Australia; 2 Department of Biochemistry and Molecular Biology Monash University Clayton Vic. Australia; 3 Peter MacCallum Cancer Centre Melbourne Vic. Australia
  5. [5] 3 Peter MacCallum Cancer Centre Melbourne Vic. Australia
  6. [6] 3 Peter MacCallum Cancer Centre Melbourne Vic. Australia; 4 Sir Peter MacCallum Department of Oncology The University of Melbourne Melbourne Vic. Australia
  7. [7] 3 Peter MacCallum Cancer Centre Melbourne Vic. Australia; 5 Department of Microbiology and Immunology The University of Melbourne Melbourne Vic. Australia; 6 Peter Doherty Institute for Infection and Immunity Melbourne Vic. Australia
  8. [8] 1 Monash Biomedicine Discovery Institute Monash University Clayton Vic. Australia; 2 Department of Biochemistry and Molecular Biology Monash University Clayton Vic. Australia

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 39, Nº. 2, 2020
• Idioma: inglés
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  • 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.