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

• Published in: Nature immunology Vol. 24; no. 1; pp. 55 - 68
• Main Authors: Christofides, Anthos, Katopodi, Xanthi-Lida, Cao, Carol, Karagkouni, Dimitra, Aliazis, Konstantinos, Yenyuwadee, Sasitorn, Aksoylar, Halil-Ibrahim, Pal, Rinku, Mahmoud, Mohamed A. A., Strauss, Laura, Tijaro-Ovalle, Natalia M., Boon, Louis, Asara, John, Vlachos, Ioannis S., Patsoukis, Nikolaos, Boussiotis, Vassiliki A.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-01-2023; Nature Publishing Group
• Subjects: 631/250; 631/250/580; Animals; Antitumor activity; Biomedical and Life Sciences; Biomedicine; Bone marrow; Cell activation; Cell Differentiation; Clonal deletion; Gene expression; Gene set enrichment analysis; Granulocyte-macrophage colony-stimulating factor; Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Immunology; Immunostimulation; Infectious Diseases; Kinases; Lymphocytes T; Macrophages; Mice; Monocytes; Myeloid Cells; Neoplasms; PD-1 protein; Phosphatase; Phosphorylation; Programmed Cell Death 1 Receptor - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Protein-tyrosine-phosphatase; SHP-2 protein; Signal Transduction; Suppressor cells; Transcription factors
• ISSN: 1529-2908; 1529-2916; 1529-2916
• DOI: 10.1038/s41590-022-01385-x

The inhibitory receptor PD-1 suppresses T cell activation by recruiting the phosphatase SHP-2. However, mice with a T-cell-specific deletion of SHP-2 do not have improved antitumor immunity. Here we showed that mice with conditional targeting of SHP-2 in myeloid cells, but not in T cells, had diminished tumor growth. RNA sequencing (RNA-seq) followed by gene set enrichment analysis indicated the presence of polymorphonuclear myeloid-derived suppressor cells and tumor-associated macrophages (TAMs) with enriched gene expression profiles of enhanced differentiation, activation and expression of immunostimulatory molecules. In mice with conditional targeting of PD-1 in myeloid cells, which also displayed diminished tumor growth, TAMs had gene expression profiles enriched for myeloid differentiation, activation and leukocyte-mediated immunity displaying >50% overlap with enriched profiles of SHP-2-deficient TAMs. In bone marrow, GM-CSF induced the phosphorylation of PD-1 and recruitment of PD-1-SHP-2 to the GM-CSF receptor. Deletion of SHP-2 or PD-1 enhanced GM-CSF-mediated phosphorylation of the transcription factors HOXA10 and IRF8, which regulate myeloid differentiation and monocytic-moDC lineage commitment, respectively. Thus, SHP-2 and PD-1-SHP-2 signaling restrained myelocyte differentiation resulting in a myeloid landscape that suppressed antitumor immunity.
Boussiotis and colleagues show that the tyrosine phosphatase SHP-2 regulates the differentiation and antitumor function of monocytes downstream of the inhibitory PD-1 receptor.