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SHP-2 and PD-1-SHP-2 signaling regulate myeloid cell differentiation and antitumor responses.
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.
Afiliación
  • Christofides A; Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
  • Katopodi XL; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  • Cao C; Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA.
  • Karagkouni D; Department of Medicine, Yale University, New Haven, CT, USA.
  • Aliazis K; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  • Yenyuwadee S; Harvard Medical School Initiative for RNA Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
  • Aksoylar HI; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Pal R; Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
  • Mahmoud MAA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  • Strauss L; Harvard College, Cambridge, MA, USA.
  • Tijaro-Ovalle NM; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  • Boon L; Harvard Medical School Initiative for RNA Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
  • Asara J; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Vlachos IS; Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
  • Patsoukis N; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  • Boussiotis VA; Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Nat Immunol ; 24(1): 55-68, 2023 01.
Article en En | MEDLINE | ID: mdl-36581713
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factor Estimulante de Colonias de Granulocitos y Macrófagos / Neoplasias Límite: Animals Idioma: En Revista: Nat Immunol Asunto de la revista: ALERGIA E IMUNOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factor Estimulante de Colonias de Granulocitos y Macrófagos / Neoplasias Límite: Animals Idioma: En Revista: Nat Immunol Asunto de la revista: ALERGIA E IMUNOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos