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

Research output: Contribution to journalArticleResearchpeer-review

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
JournalEMBO Journal
DOIs
Publication statusAccepted/In press - 2019

Keywords

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

Cite this

Wiede, Florian ; Lu, Kun-Hui ; Du, Xin ; Liang, Shuwei ; Hochheiser, Katharina ; Dodd, Garron T ; Goh, Pei K ; Kearney, Conor ; Meyran, Deborah ; Beavis, Paul A. ; Henderson, Melissa A. ; Park, Simone L. ; Waithman, Jason ; Zhang, Sheng ; Zhang, Zhong Yin ; Oliaro, Jane ; Gebhardt, Thomas ; Darcy, Phillip K ; Tiganis, Tony. / PTPN2 phosphatase deletion in T cells promotes anti-tumour immunity and CAR T-cell efficacy in solid tumours. In: EMBO Journal. 2019.
@article{9878123157f44264b89ca93e436aa3b5,
title = "PTPN2 phosphatase deletion in T cells promotes anti-tumour immunity and CAR T-cell efficacy in solid tumours",
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 = "adoptive T-cell therapy, CAR T cells, protein tyrosine phosphatase N2, STAT-5 signalling, TCR signalling",
author = "Florian Wiede and Kun-Hui Lu and Xin Du and Shuwei Liang and Katharina Hochheiser and Dodd, {Garron T} and Goh, {Pei K} and Conor Kearney and Deborah Meyran and Beavis, {Paul A.} and Henderson, {Melissa A.} and Park, {Simone L.} and Jason Waithman and Sheng Zhang and Zhang, {Zhong Yin} and Jane Oliaro and Thomas Gebhardt and Darcy, {Phillip K} and Tony Tiganis",
year = "2019",
doi = "10.15252/embj.2019103637",
language = "English",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "John Wiley & Sons",

}

Wiede, F, Lu, K-H, Du, X, Liang, S, Hochheiser, K, Dodd, GT, Goh, PK, Kearney, C, Meyran, D, Beavis, PA, Henderson, MA, Park, SL, Waithman, J, Zhang, S, Zhang, ZY, Oliaro, J, Gebhardt, T, Darcy, PK & Tiganis, T 2019, 'PTPN2 phosphatase deletion in T cells promotes anti-tumour immunity and CAR T-cell efficacy in solid tumours', EMBO Journal. https://doi.org/10.15252/embj.2019103637

PTPN2 phosphatase deletion in T cells promotes anti-tumour immunity and CAR T-cell efficacy in solid tumours. / Wiede, Florian; Lu, Kun-Hui; Du, Xin; Liang, Shuwei; Hochheiser, Katharina; Dodd, Garron T; Goh, Pei K; Kearney, Conor; Meyran, Deborah; Beavis, Paul A.; Henderson, Melissa A.; Park, Simone L.; Waithman, Jason; Zhang, Sheng; Zhang, Zhong Yin; Oliaro, Jane; Gebhardt, Thomas; Darcy, Phillip K; Tiganis, Tony.

In: EMBO Journal, 2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - PTPN2 phosphatase deletion in T cells promotes anti-tumour immunity and CAR T-cell efficacy in solid tumours

AU - Wiede, Florian

AU - Lu, Kun-Hui

AU - Du, Xin

AU - Liang, Shuwei

AU - Hochheiser, Katharina

AU - Dodd, Garron T

AU - Goh, Pei K

AU - Kearney, Conor

AU - Meyran, Deborah

AU - Beavis, Paul A.

AU - Henderson, Melissa A.

AU - Park, Simone L.

AU - Waithman, Jason

AU - Zhang, Sheng

AU - Zhang, Zhong Yin

AU - Oliaro, Jane

AU - Gebhardt, Thomas

AU - Darcy, Phillip K

AU - Tiganis, Tony

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

KW - adoptive T-cell therapy

KW - CAR T cells

KW - protein tyrosine phosphatase N2

KW - STAT-5 signalling

KW - TCR signalling

UR - http://www.scopus.com/inward/record.url?scp=85076152596&partnerID=8YFLogxK

U2 - 10.15252/embj.2019103637

DO - 10.15252/embj.2019103637

M3 - Article

AN - SCOPUS:85076152596

JO - EMBO Journal

JF - EMBO Journal

SN - 0261-4189

M1 - e103637

ER -