美国哈佛医学院Vassiliki A. Boussiotis研究组发现，SHP-2和PD-1-SHP-2信号传递调节骨髓细胞分化和抗肿瘤反应。相关论文于2022年12月29日在线发表于国际学术期刊《自然—免疫学》上。

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

Author: 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.

Issue&Volume: 2022-12-29

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.

DOI: 10.1038/s41590-022-01385-x

Source: https://www.nature.com/articles/s41590-022-01385-x