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

ABSTRACT:

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.

SUBMITTER: Tan TG

PROVIDER: S-EPMC9756846 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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

Tan Tze Guan TG Zybina Yulia Y McKenna Cooper C Olow Aleksandra A Rukmini Subhadra Jayaraman SJ Wong Michael Thomas MT Sadekova Svetlana S Chackerian Alissa A Bauché David D

Frontiers in oncology 20221202

<h4>Introduction</h4>Colorectal cancer (CRC) is largely refractory to currently available immunotherapies such as blockade of programmed cell death protein-1 (PD-1).<h4>Results</h4>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 ...[more]

PMID: 36531014

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