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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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 number103637
Number of pages26
JournalEMBO Journal
DOIs
Publication statusE-pub ahead of print - 5 Dec 2019

Cite this

Wiede, F., Lu, K-H., Du, X., Liang, S., Hochheiser, K., Dodd, G. T., Goh, P. K., Kearney, C., Meyran, D., Beavis, P. A., Henderson, M. A., Park, S. L., Waithman, J., Zhang, S., Zhang, Z-Y., Oliaro, J., Gebhardt, T., Darcy, P. K., & Tiganis, T. (2019). PTPN2 phosphatase deletion in T cells promotes anti-tumour immunity and CAR T-cell efficacy in solid tumours. EMBO Journal, [103637]. https://doi.org/10.15252/embj.2019103637