Protein tyrosine phosphatase nonreceptor type 2 controls colorectal cancer development
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
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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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 5

CD8+ T cells are the key drivers of tumor reduction.

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CD8+ T cells are the key drivers of tumor reduction. MC38 tumor cells (3...
MC38 tumor cells (300,000 cells) were injected s.c. into WT and Ptpn2fl/fl Cd4Cre+/– mice. (A) Representative image of MC38-induced tumors from WT and Ptpn2fl/fl Cd4Cre+/– mice. (B) MC38-induced tumor development (n = 5 WT mice and 10 tumors; n = 4 Ptpn2fl/fl Cd4Cre+/– mice and 8 tumors) over time and tumor weights on the last day of the experiment. P values were determined by 2-tailed Mann-Whitney U test. (C) Scheme of CD8+ T cell depletion and image of representative tumors from IgG isotype control– and anti-CD8–treated WT and Ptpn2fl/fl Cd4Cre+/– mice. (D) Tumor sizes and weights (n = 6 WT IgG–treated mice and 12 tumors; n = 10 mice and 20 tumors for IgG-treated Ptpn2fl/fl Cd4Cre+/– mice, anti-CD8–treated WT mice, and anti-CD8–treated Ptpn2fl/fl Cd4Cre+/– mice; n = 2 independent experiments). P values were determined by 1-way ANOVA with Tukey’s multiple-comparison test. (E) Representative images and quantification of IHC and flow cytometric CD8 staining of WT and Ptpn2fl/fl Cd4Cre+/– mouse tumor tissue from IgG control– and anti–CD8–treated groups. Scale bars: 50 μm. P values were determined by 1-way ANOVA with Tukey’s multiple-comparison test. (F) Inverse correlation of tumor weight and frequency of CD8+ T cells in tumor tissue from WT and Ptpn2fl/fl Cd4Cre+/– mice. P and R2 values were determined by linear regression analysis. (G) Representative gross image of MC38 tumors from IgG isotype control– and anti-CD4–treated WT and Ptpn2fl/fl Cd4Cre+/– mice. (H) Tumor development (n = 5 mice and 10 tumors per group). P values were determined by 1-way ANOVA with Tukey’s multiple-comparison test. Data represent the mean ± SD.