PTPN2 elicits cell autonomous and non-cell autonomous effects on antitumor immunity in triple-negative breast cancer

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• The tumor suppressor PTPN2 is often diminished in triple-negative breast cancer (TNBC).
• PTPN2 deficiency can paradoxically enhance antitumor immunity by promoting T cell activity.
• Understanding PTPN2's role is crucial for developing novel TNBC therapies.

Purpose of the Study:

• To explore the therapeutic potential of targeting PTPN2 in both tumor cells and T cells for TNBC treatment.
• To investigate the association between PTPN2 levels, T cell infiltration, and PD-L1 expression in TNBC.
• To evaluate the impact of PTPN2 deletion on tumor growth and immunotherapy efficacy.

Main Methods:

• Analysis of PTPN2 expression in TNBC patient samples and its correlation with survival and T cell infiltrates.
• Generation of murine mammary epithelial cell TNBC models with PTPN2 deletion.
• Assessment of STAT-1-dependent T cell recruitment and PD-L1 expression following PTPN2 deletion.
• Evaluation of combined PTPN2 deletion in tumor and T cells on tumor growth and T cell exhaustion.

Main Results:

• Low PTPN2 expression in TNBC correlated with increased T cell infiltrates, PD-L1 expression, and improved patient survival.
• PTPN2 deletion in murine TNBC models enhanced STAT-1-dependent T cell recruitment and PD-L1 expression, repressing tumor growth.
• Combined PTPN2 deletion in tumors and T cells further repressed tumor growth and ablated tumors with exhausted T cells.
• Targeting PTPN2 enhanced the efficacy of anti-PD-1 immunotherapy.

Conclusions:

• PTPN2 deficiency in TNBC promotes T cell recruitment and activation, contributing to antitumor immunity.
• Targeting PTPN2 in tumor cells and/or T cells represents a promising therapeutic strategy for TNBC.
• PTPN2 inhibition can overcome inhibitory constraints on T cells, enhancing cancer immunotherapy effectiveness.