Concomitant deletion of Ptpn6 and Ptpn11 in T cells fails to improve anticancer responses

TY - JOUR

T1 - Concomitant deletion of Ptpn6 and Ptpn11 in T cells fails to improve anticancer responses

AU - Ventura, Pedro M. O.

AU - Gakovic, Milica

AU - Fischer, Berenice A.

AU - Spinelli, Laura

AU - Rota, Giorgia

AU - Pathak, Shalini

AU - Khameneh, Hanif J.

AU - Zenobi, Alessandro

AU - Thomson, Sarah

AU - Birchmeier, Walter

AU - Cantrell, Doreen A.

AU - Guarda, Greta

N1 - Funding Information: We thank Irene Buzzago, David Jarrossay, Matteo Pecoraro, and the Animal Facility collaborators for precious help and technical advice at the IRB, Bellinzona, and Douglas Fearon, Cambridge, and Eric Vivier Marseille, for reagents and advice. We thank E. Emslie for technical assistance with mouse genotyping, A. Gardner, A. Rennie, and R. Clarke from the Flow Cytometry facility for cell sorting, M. Gierlinski for help with statistical analysis, the Fingerprint proteomics facility for the mass spectrometry and advice on proteomics, and the Biological Services Resource unit at the University of Dundee. Graphical abstract and some figure panels were created with Biorender. This work was supported by the Swiss National Science Foundation (310030_185185 and 310030_197771 to GG), the Fondazione San Salvatore, Lugano, the Swiss Cancer Research Foundation (KFS 5141‐08‐2020 to GG), the Leonardo Foundation, Lugano, the Novartis Foundation, Basel. This research was supported by a Wellcome Trust Principal Research Fellowship to DAC (205023/Z/16/Z). , Publisher Copyright: ©2022 The Authors. Published under the terms of the CC BY 4.0 license.

PY - 2022/11/7

Y1 - 2022/11/7

N2 - Anticancer T cells acquire a dysfunctional state characterized by poor effector function and expression of inhibitory receptors, such as PD-1. Blockade of PD-1 leads to T cell reinvigoration and is increasingly applied as an effective anticancer treatment. Recent work challenged the commonly held view that the phosphatase PTPN11 (known as SHP-2) is essential for PD-1 signaling in T cells, suggesting functional redundancy with the homologous phosphatase PTPN6 (SHP-1). Therefore, we investigated the effect of concomitant Ptpn6 and Ptpn11 deletion in T cells on their ability to mount antitumour responses. In vivo data show that neither sustained nor acute Ptpn6/11 deletion improves T cell-mediated tumor control. Sustained loss of Ptpn6/11 also impairs the therapeutic effects of anti-PD1 treatment. In vitro results show that Ptpn6/11-deleted CD8+ T cells exhibit impaired expansion due to a survival defect and proteomics analyses reveal substantial alterations, including in apoptosis-related pathways. These data indicate that concomitant ablation of Ptpn6/11 in polyclonal T cells fails to improve their anticancer properties, implying that caution shall be taken when considering their inhibition for immunotherapeutic approaches.

AB - Anticancer T cells acquire a dysfunctional state characterized by poor effector function and expression of inhibitory receptors, such as PD-1. Blockade of PD-1 leads to T cell reinvigoration and is increasingly applied as an effective anticancer treatment. Recent work challenged the commonly held view that the phosphatase PTPN11 (known as SHP-2) is essential for PD-1 signaling in T cells, suggesting functional redundancy with the homologous phosphatase PTPN6 (SHP-1). Therefore, we investigated the effect of concomitant Ptpn6 and Ptpn11 deletion in T cells on their ability to mount antitumour responses. In vivo data show that neither sustained nor acute Ptpn6/11 deletion improves T cell-mediated tumor control. Sustained loss of Ptpn6/11 also impairs the therapeutic effects of anti-PD1 treatment. In vitro results show that Ptpn6/11-deleted CD8+ T cells exhibit impaired expansion due to a survival defect and proteomics analyses reveal substantial alterations, including in apoptosis-related pathways. These data indicate that concomitant ablation of Ptpn6/11 in polyclonal T cells fails to improve their anticancer properties, implying that caution shall be taken when considering their inhibition for immunotherapeutic approaches.

KW - PD-1 checkpoint blockade

KW - Ptpn11

KW - Ptpn6

KW - T cell exhaustion

KW - Cancer

KW - Immunology

KW - Signal Transduction

UR - https://www.scopus.com/pages/publications/85139221253

U2 - 10.15252/embr.202255399

DO - 10.15252/embr.202255399

M3 - Article

C2 - 36194675

SN - 1469-221X

VL - 23

JO - EMBO Reports

JF - EMBO Reports

IS - 11

M1 - e55399

ER -