1196048_Goh,P_2022.pdf (5.23 MB)
PTPN2 elicits cell autonomous and non–cell autonomous effects on antitumor immunity in triple-negative breast cancer
journal contributionposted on 2022-06-22, 05:01 authored by PK Goh, F Wiede, MN Zeissig, KL Britt, S Liang, T Molloy, N Goode, R Xu, S Loi, M Muller, Patrick HumbertPatrick Humbert, C McLean, T Tiganis
The tumor-suppressor PTPN2 is diminished in a subset of triple-negative breast cancers (TNBCs). Paradoxically, PTPN2-deficiency in tumors or T cells in mice can facilitate T cell recruitment and/or activation to promote antitumor immunity. Here, we explored the therapeutic potential of targeting PTPN2 in tumor cells and T cells. PTPN2-deficiency in TNBC associated with T cell infiltrates and PD-L1 expression, whereas low PTPN2 associated with improved survival. PTPN2 deletion in murine mammary epithelial cells TNBC models, did not promote tumorigenicity but increased STAT-1–dependent T cell recruitment and PD-L1 expression to repress tumor growth and enhance the efficacy of anti-PD-1. Furthermore, the combined deletion of PTPN2 in tumors and T cells facilitated T cell recruitment and activation and further repressed tumor growth or ablated tumors already predominated by exhausted T cells. Thus, PTPN2-targeting in tumors and/or T cells facilitates T cell recruitment and/or alleviates inhibitory constraints on T cells to combat TNBC.
This work was supported by the Austrian Science Fund FWF (SFB F6101 and F6106 to M.M.), Worldwide Cancer Research (18-0045 to T.T. and C.M.), the U.S. Army Department of Defense (BC200609 to T.T.), and the NHMRC of Australia (APP1003037 to T.T.).
Article NumberARTN eabk3338
PublisherAmerican Association for the Advancement of Science (AAAS)
Rights Statement© 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
Science & TechnologyMultidisciplinary SciencesScience & Technology - Other TopicsPROTEIN-TYROSINE-PHOSPHATASETUMOR-INFILTRATING LYMPHOCYTESMEDIATED GENE DELETIONACTIVATIONPROMOTESOBESITYSTAT1EXPRESSIONGENERATIONRELEVANCEAnimalsB7-H1 AntigenCell Line, TumorHumansMiceProtein Tyrosine Phosphatase, Non-Receptor Type 2Triple Negative Breast NeoplasmsOncology and Carcinogenesis not elsewhere classifiedCancer Cell Biology