Protein tyrosine phosphatase nonreceptor type 2 controls colorectal cancer development
Egle Katkeviciute, … , Michael Scharl, Marianne R. Spalinger
Egle Katkeviciute, … , Michael Scharl, Marianne R. Spalinger
Published October 1, 2020
Citation Information: J Clin Invest. 2021;131(1):e140281. https://doi.org/10.1172/JCI140281.
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Research Article Gastroenterology Oncology

Protein tyrosine phosphatase nonreceptor type 2 controls colorectal cancer development

Abstract

Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) recently emerged as a promising cancer immunotherapy target. We set out to investigate the functional role of PTPN2 in the pathogenesis of human colorectal carcinoma (CRC), as its role in immune-silent solid tumors is poorly understood. We demonstrate that in human CRC, increased PTPN2 expression and activity correlated with disease progression and decreased immune responses in tumor tissues. In particular, stage II and III tumors displayed enhanced PTPN2 protein expression in tumor-infiltrating T cells, and increased PTPN2 levels negatively correlated with expression of PD-1, CTLA4, STAT1, and granzyme A. In vivo, T cell– and DC-specific PTPN2 deletion reduced tumor burden in several CRC models by promoting CD44+ effector/memory T cells, as well as CD8+ T cell infiltration and cytotoxicity in the tumor. In direct relevance to CRC treatment, T cell–specific PTPN2 deletion potentiated anti–PD-1 efficacy and induced antitumor memory formation upon tumor rechallenge in vivo. Our data suggest a role for PTPN2 in suppressing antitumor immunity and promoting tumor development in patients with CRC. Our in vivo results identify PTPN2 as a key player in controlling the immunogenicity of CRC, with the strong potential to be exploited for cancer immunotherapy.

Authors

Egle Katkeviciute, Larissa Hering, Ana Montalban-Arques, Philipp Busenhart, Marlene Schwarzfischer, Roberto Manzini, Javier Conde, Kirstin Atrott, Silvia Lang, Gerhard Rogler, Elisabeth Naschberger, Vera S. Schellerer, Michael Stürzl, Andreas Rickenbacher, Matthias Turina, Achim Weber, Sebastian Leibl, Gabriel E. Leventhal, Mitchell Levesque, Onur Boyman, Michael Scharl, Marianne R. Spalinger

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Figure 2

PTPN2 deletion in T cells leads to reduced tumor burden in colitis-associated tumors.

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PTPN2 deletion in T cells leads to reduced tumor burden in colitis-assoc...
Tumors were induced in Ptpn2fl/fl Cd4Cre+/– mice (ΔT) (n = 10) and littermate control Ptpn2fl/fl mice (WT) (n = 12) using the AOM/DSS model (n = 2 independent experiments). Mixed WT controls (Ptpn2fl/fl Cd4Cre– and Ptpn2fl/fl Cd11cCre–) were used in this experiment. (A) Schematic overview of the experimental procedure. (B) Representative colonoscopy images from untreated and AOM/DSS-treated mice. (C) Quantification of the total number of tumors, stratified by tumor size. P values were determined by 2-tailed Mann-Whitney U test. (D) H&E staining of tumor tissue from Ptpn2fl/fl Cd4Cre+/– and Ptpn2fl/fl mice. Scale bars: 100 μm. (E) Representative images and quantification of CD3 staining in Ptpn2fl/fl Cd4Cre+/– and WT tumor tissue. RNA-Seq was performed on untreated, inflamed nontumor, and inflamed tumor tissue from WT and Ptpn2fl/fl Cd4Cre+/– mice (n = 4 mice each). Scale bars: 50 μm. P values were determined by 1-way ANOVA with Tukey’s multiple-comparison test. (F) Heatmap of mRNA expression levels of T cell–related genes from WT inflamed nontumor tissue (WT non-T), WT inflamed tumor tissue (WT T), Ptpn2fl/fl Cd4Cre+/– untreated tissue (ΔT), Ptpn2fl/fl Cd4Cre+/– inflamed nontumor tissue (ΔT non-T), and Ptpn2fl/fl Cd4Cre+/– inflamed tumor tissue (ΔT T) normalized to the expression levels in colon tissue from water-treated WT mice. False sign rate, *P < 0.01, **P < 0.001, and ***P < 0.0001. Data represent the mean ± SD.