SHP-2 and PD-1-SHP-2 signaling regulate myeloid cell differentiation and antitumor responses
2
Issued Date
2023-01-01
Resource Type
ISSN
15292908
eISSN
15292916
Scopus ID
2-s2.0-85145036119
Pubmed ID
36581713
Journal Title
Nature Immunology
Volume
24
Issue
1
Start Page
55
End Page
68
Rights Holder(s)
SCOPUS
Bibliographic Citation
Nature Immunology Vol.24 No.1 (2023) , 55-68
Suggested Citation
Christofides A., Katopodi X.L., Cao C., Karagkouni D., Aliazis K., Yenyuwadee S., Aksoylar H.I., Pal R., Mahmoud M.A.A., Strauss L., Tijaro-Ovalle N.M., Boon L., Asara J., Vlachos I.S., Patsoukis N., Boussiotis V.A. SHP-2 and PD-1-SHP-2 signaling regulate myeloid cell differentiation and antitumor responses. Nature Immunology Vol.24 No.1 (2023) , 55-68. 68. doi:10.1038/s41590-022-01385-x Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/81984
Title
SHP-2 and PD-1-SHP-2 signaling regulate myeloid cell differentiation and antitumor responses
Other Contributor(s)
Abstract
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.