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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

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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 1

Enhanced PTPN2 expression in human CRC.

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Enhanced PTPN2 expression in human CRC.
(A) Representative images and qu...
(A) Representative images and quantification of PTPN2 IHC staining in nontumor (Non T) and stage I–IV tumor tissue. Scale bars: 50 μm. P values were determined by 1-way ANOVA with Tukey’s multiple-comparison test. Data represent the mean ± SD. (B) PTPN2 phosphatase activity in nontumor and tumor tissue (n = 10 samples per condition). P values were determined by 2-tailed Mann-Whitney U test. (C) Correlation between PTPN2 and p-STAT1 protein quantification and (D) immunofluorescence costaining for CD3 (AF594, green), PTPN2 (AF647, red), and DAPI. Original magnification, 40×; zoom factor, 3.0. P and R2 values in C were determined by linear regression analysis. (E) Correlations between PTPN2 and STAT1 and between CXCL11 and GZMA mRNA expression. P and R2 values were determined by linear regression analysis. (F) Representative images of IHC and correlations between PTPN2 and the checkpoint molecule PD-1 in primary CRC. Scale bars: 100 μm. P values and R2 values were determined by linear regression analysis. HPF, high-power field.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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