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SPATA2 and CYLD inhibit T cell infiltration into colorectal cancer via regulation of IFN-γ/STAT1 axis

INTRODUCTION: Colorectal cancer (CRC) is largely refractory to currently available immunotherapies such as blockade of programmed cell death protein-1 (PD-1). RESULTS: In this study, we identified SPATA2 and its protein partner CYLD as novel regulators of CXC-ligand 10 (CXCL10), a T-cell-attractant...

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Autores principales: Tan, Tze Guan, Zybina, Yulia, McKenna, Cooper, Olow, Aleksandra, Rukmini, Subhadra Jayaraman, Wong, Michael Thomas, Sadekova, Svetlana, Chackerian, Alissa, Bauché, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9756846/
https://www.ncbi.nlm.nih.gov/pubmed/36531014
http://dx.doi.org/10.3389/fonc.2022.1016307
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author Tan, Tze Guan
Zybina, Yulia
McKenna, Cooper
Olow, Aleksandra
Rukmini, Subhadra Jayaraman
Wong, Michael Thomas
Sadekova, Svetlana
Chackerian, Alissa
Bauché, David
author_facet Tan, Tze Guan
Zybina, Yulia
McKenna, Cooper
Olow, Aleksandra
Rukmini, Subhadra Jayaraman
Wong, Michael Thomas
Sadekova, Svetlana
Chackerian, Alissa
Bauché, David
author_sort Tan, Tze Guan
collection PubMed
description INTRODUCTION: Colorectal cancer (CRC) is largely refractory to currently available immunotherapies such as blockade of programmed cell death protein-1 (PD-1). RESULTS: In this study, we identified SPATA2 and its protein partner CYLD as novel regulators of CXC-ligand 10 (CXCL10), a T-cell-attractant chemokine, in CRC. By specifically deleting SPATA2 and CYLD in human and mouse CRC cell lines, we showed that these two proteins inhibit STAT1 accumulation and activation and subsequently CXCL10 expression in tumor cells. At steady-state, STAT1 is highly ubiquitinated in a SPATA2/CYLD-dependent manner. Finally, we demonstrated that tumor-specific deletion of SPATA2 and CYLD enhances anti-PD-1 response in vivo. DISCUSSION: Our data suggest that SPATA2 and CYLD represent two potential novel targets for treatment of immune-excluded, PD-1-resistant tumors.
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spelling pubmed-97568462022-12-17 SPATA2 and CYLD inhibit T cell infiltration into colorectal cancer via regulation of IFN-γ/STAT1 axis Tan, Tze Guan Zybina, Yulia McKenna, Cooper Olow, Aleksandra Rukmini, Subhadra Jayaraman Wong, Michael Thomas Sadekova, Svetlana Chackerian, Alissa Bauché, David Front Oncol Oncology INTRODUCTION: Colorectal cancer (CRC) is largely refractory to currently available immunotherapies such as blockade of programmed cell death protein-1 (PD-1). RESULTS: In this study, we identified SPATA2 and its protein partner CYLD as novel regulators of CXC-ligand 10 (CXCL10), a T-cell-attractant chemokine, in CRC. By specifically deleting SPATA2 and CYLD in human and mouse CRC cell lines, we showed that these two proteins inhibit STAT1 accumulation and activation and subsequently CXCL10 expression in tumor cells. At steady-state, STAT1 is highly ubiquitinated in a SPATA2/CYLD-dependent manner. Finally, we demonstrated that tumor-specific deletion of SPATA2 and CYLD enhances anti-PD-1 response in vivo. DISCUSSION: Our data suggest that SPATA2 and CYLD represent two potential novel targets for treatment of immune-excluded, PD-1-resistant tumors. Frontiers Media S.A. 2022-12-02 /pmc/articles/PMC9756846/ /pubmed/36531014 http://dx.doi.org/10.3389/fonc.2022.1016307 Text en Copyright © 2022 Tan, Zybina, McKenna, Olow, Rukmini, Wong, Sadekova, Chackerian and Bauché https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Tan, Tze Guan
Zybina, Yulia
McKenna, Cooper
Olow, Aleksandra
Rukmini, Subhadra Jayaraman
Wong, Michael Thomas
Sadekova, Svetlana
Chackerian, Alissa
Bauché, David
SPATA2 and CYLD inhibit T cell infiltration into colorectal cancer via regulation of IFN-γ/STAT1 axis
title SPATA2 and CYLD inhibit T cell infiltration into colorectal cancer via regulation of IFN-γ/STAT1 axis
title_full SPATA2 and CYLD inhibit T cell infiltration into colorectal cancer via regulation of IFN-γ/STAT1 axis
title_fullStr SPATA2 and CYLD inhibit T cell infiltration into colorectal cancer via regulation of IFN-γ/STAT1 axis
title_full_unstemmed SPATA2 and CYLD inhibit T cell infiltration into colorectal cancer via regulation of IFN-γ/STAT1 axis
title_short SPATA2 and CYLD inhibit T cell infiltration into colorectal cancer via regulation of IFN-γ/STAT1 axis
title_sort spata2 and cyld inhibit t cell infiltration into colorectal cancer via regulation of ifn-γ/stat1 axis
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9756846/
https://www.ncbi.nlm.nih.gov/pubmed/36531014
http://dx.doi.org/10.3389/fonc.2022.1016307
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