Christofides et al. used myeloid cell-specific knockout of SHP-2 phosphatase and PD-1 to demonstrate an important role of both molecules in control of MDSC and TAM differentiation toward an immunosuppressive phenotype during early myelopoiesis. Conditional knockouts led to a functional and transcriptomic shift – mediated by transcription factors HOXA10 and IRF8 – toward enhanced antigen presentation, leading to T cell activation and a direct antitumor, proinflammatory phenotype, which was transferable to naive mice (trained immunity). IL-10, often considered an anti-inflammatory mediator, was important to the direct antitumor effects.
Contributed by Ed Fritsch
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.
Author Info: (1) Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Bo
Author Info: (1) Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Department of Medicine, Yale University, New Haven, CT, USA. (2) Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Harvard Medical School Initiative for RNA Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (3) Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Harvard College, Cambridge, MA, USA. (4) Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Harvard Medical School Initiative for RNA Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (5) Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. (6) Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Department of Dermatology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. (7) Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. (8) Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. (9) Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Heidelberg University, German Cancer Research Center (DKFZ), Heidelberg, Germany. (10) Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Sanofi /Tidal, Cambridge, MA, USA. (11) Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Department of Medicine, Yale University, New Haven, CT, USA. (12) JJP Biologics, Warsaw, Poland. (13) Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. (14) Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Harvard Medical School Initiative for RNA Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA. (15) Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. (16) Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA. vboussio@bidmc.harvard.edu. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. vboussio@bidmc.harvard.edu. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. vboussio@bidmc.harvard.edu.
