The effects of PD-1 on tumor-mediated “emergency” myelopoiesis and fate commitment of myeloid cells: Implications for anti-tumor immunity

PD-1 对肿瘤介导的“紧急”骨髓生成和骨髓细胞命运决定的影响：抗肿瘤免疫的意义

• 批准号: 10330481
• 负责人: VASSILIKI A BOUSSIOTIS
• 金额: $ 59.12万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-10 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10330481
• 关键词: ATAC-seq; Ablation; Affect; Antibodies; B-Lymphocytes; Biogenesis; Blocking Antibodies; CD8-Positive T-Lymphocytes; Cancer Patient; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; ChIP-seq; Clinical Trials; Dendritic Cells; Emergency Situation; Environment; Epigenetic Process; FRAP1 gene; Generations; Genes; Genetic; Growth Factor Receptors; Hematopoietic; Hematopoietic stem cells; ITGAM gene; Immune; Immune system; Immunity; Immunologics; Immunotherapy; Innate Immune System; Interferons; Interleukin-17; Knockout Mice; Knowledge; Lead; Ligands; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; Myeloid Progenitor Cells; Myeloid-derived suppressor cells; Myelopoiesis; Outcome; Output; PD-1 blockade; PD-1 pathway; PDL1 pathway; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Pharmacology; Phosphorylation; Property; Regulatory T-Lymphocyte; Role; Signal Transduction; Stress; T cell response; T-Lymphocyte; Training; Tumor Immunity; Work; anti-cancer therapeutic; cancer cell; cancer therapy; cholesterol biosynthesis; glucose uptake; granulocyte; immune activation; improved outcome; inhibitor; macrophage; metabolomics; mevalonate; monocyte; myeloid cell development; novel; pathogen; preservation; prevent; progenitor; programmed cell death ligand 1; programmed cell death protein 1; programs; response; stable isotope; success; terminally differentiated effector memory (TEM) T cells; transcriptome sequencing; tumor; tumor growth; tumor microenvironment

PD-1 blocking agents have achieved significant success as anti-cancer therapeutics. The mechanism(s) of how PD-1 compromises anti-tumor function remain poorly understood. We generated an antibody that recognizes PD-1pY248 that is required for PD-1 inhibitory signaling. In three mouse tumor models, we identified PD-1 expression and phosphorylation in CD4+ and CD8+ T cells of the tumor microenvironment (TME) but more prominently in myeloid cells. These findings prompted us to examine the role of PD-1 in myeloid cell differentiation and function in cancer immunity. The rapid change in hematopoietic cell output that occurs in response to immunologic stress is known as “emergency” myelopoiesis”. During continuous low-level stimulation mediated by cancer-derived factors, common myeloid progenitors (CMP) and granulocyte/macrophage progenitors (GMP), undergo modest but continuous expansion with hindered differentiation leading to the output of immature myeloid-derived suppressor cells (MDSC). We analyzed the myeloid compartment of tumor-bearing mice and determined that myeloid cells that expand during cancer-driven emergency myelopoiesis express PD- 1 and PD-L1. Using PD-1 KO mice or WT mice treated with PD-1 blocking antibody we determined that PD-1 deletion or blockade prevented the accumulation of immature myeloid progenitor cells and stimulated differentiation and output of Ly6Chi effector monocytes, macrophages and dendritic cells (DC). To determine whether these outcomes were mediated by a myeloid-intrinsic impact of PD-1 ablation or by the effects of PD- 1neg T cells on myeloid cells, we generated mice with conditional targeting of the Pdcd1 gene (PD-1f/f) and selectively eliminated PD-1 in myeloid cells or T cells. Compared to T cell-specific, myeloid cell-specific PD-1 ablation more effectively decreased tumor growth. Cancer-driven emergency myelopoiesis was differentially affected. Both myeloid-specific and T cell-specific PD-1 ablation resulted in expansion and accumulation of CMP but only myeloid-specific PD-1 ablation prevented the accumulation of GMP and switched the myeloid cell fate from MDSCs to differentiated effector monocytes, macrophages, DC. Our findings reveal a previously unidentified role of the PD-1: PD-L1 pathway and support the novel hypothesis that switch of myeloid cell fate commitment might be a key mechanism by which PD-1 blockade mediates its anti-tumor function. To investigate this, we will pursue the following specific aims to determine: 1. How PD-1 signaling mediates lineage fate determination of myeloid progenitor cells in response to emergency myelopoiesis. 2. How PD-1 targeting impacts the metabolic and epigenetic program of myeloid cells. 3. How PD-1 affects anti-tumor immunity by regulating the crosstalk between innate and tumor- associated T cells.

PD-1阻断剂作为抗癌药物已经取得了显著的成功。机制(s)如何