DUSP22 dephosphorylates LGALS1 to enhance T cell-driven antitumor immunity

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Insufficient CD8+ T cell infiltration in the tumor microenvironment (TME) limits antitumor immunity and immunotherapy effectiveness.
• Identifying novel tumor cell-intrinsic regulators of T cell infiltration is crucial for enhancing cancer treatments.

Purpose of the Study:

• To identify novel tumor cell-intrinsic regulators of T cell infiltration.
• To elucidate the mechanisms by which these regulators affect T cell infiltration and function.

Main Methods:

• Genome-wide Sleeping Beauty transposon mutagenesis screen in murine breast cancer models.
• Mass spectrometry, co-immunoprecipitation, qPCR, western blotting, flow cytometry, IHC, multiplex IHC, and RNA sequencing were used to assess protein interactions, gene/protein expression, and T cell infiltration.
• In vitro and in vivo models were used to validate T cell infiltration and the DUSP22-LGALS1 axis.

Main Results:

• Dual-specificity phosphatase 22 (DUSP22) expression correlated with enhanced CD8+ T cell accumulation and suppressed tumor progression.
• DUSP22 dephosphorylates LGALS1, leading to its degradation and reduced immunosuppression, thereby increasing CD8+ T cell infiltration and function.
• LGALS1 expression was negatively correlated with DUSP22 levels and CD8+ T cell infiltration in human breast cancer samples.

Conclusions:

• A novel phosphorylation-dependent DUSP22-LGALS1 axis was identified, which reprograms the immunosuppressive TME.
• Targeting the DUSP22-LGALS1 axis enhances CD8+ T cell infiltration and synergizes with anti-PD-1 therapy, offering a promising strategy to overcome resistance to immune checkpoint blockade in breast cancer.