SHP-2 and PD-1-SHP-2 signaling regulate myeloid cell differentiation and antitumor responses

Area of Science:

• Immunology
• Cancer Biology
• Cellular Signaling

Background:

• The programmed cell death protein 1 (PD-1) receptor inhibits T cell activation by recruiting the SH2-containing protein tyrosine phosphatase 2 (SHP-2).
• Previous studies showed T-cell-specific deletion of SHP-2 did not improve antitumor immunity, suggesting alternative roles for SHP-2 in cancer.

Purpose of the Study:

• To investigate the role of SHP-2 and PD-1 in myeloid cells, rather than T cells, in regulating antitumor immunity.
• To elucidate the molecular mechanisms by which SHP-2 and PD-1 signaling in myeloid cells impacts the tumor microenvironment.

Main Methods:

• Generated mice with conditional knockout of SHP-2 or PD-1 specifically in myeloid cells.
• Utilized RNA sequencing (RNA-seq) and gene set enrichment analysis to profile myeloid cell populations.
• Investigated signaling pathways involving Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) receptor, PD-1, SHP-2, and key transcription factors.

Main Results:

• Conditional deletion of SHP-2 or PD-1 in myeloid cells, but not T cells, led to diminished tumor growth.
• RNA-seq analysis revealed that SHP-2 and PD-1 deficiency in myeloid cells promoted differentiation and activation of tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs).
• SHP-2 and PD-1 signaling were found to restrain GM-CSF-induced phosphorylation of transcription factors HOXA10 and IRF8, which are critical for myeloid differentiation.

Conclusions:

• SHP-2 and PD-1 signaling in myeloid cells actively suppresses antitumor immunity by inhibiting myeloid differentiation.
• Targeting myeloid SHP-2 or PD-1 can reprogram the myeloid landscape to enhance anti-tumor responses, offering potential therapeutic strategies.