Science subjournal: the understanding of PD-1 has encountered a turning point! Targeted removal of PD-1 from myeloid cells can induce antitumor immune response

January 21, 2020 / Biovalley BIOON / - -- as a T-cell checkpoint receptor, PD-1 is the main factor that inhibits T-cell response expressed on the surface of activated T cells, and therefore is the target of tumor immunotherapy It is also expressed on the surface of natural killer cells (NK cells), B cells, regulatory T cells (Treg), follicular helper T cells (TFH) and myeloid cells The current view shows that the key mechanism of inhibiting the anti-tumor immune response is the up-regulation of PD-1 ligand (PD-L1 or PD-L2, collectively referred to as PD-L1 / 2) on the cancer cells and antigen-presenting cells (APC) in the tumor microenvironment, and the binding of PD-1 ligand with PD-1 on the surface of tumor infiltrating CD8 + T cells, which results in the failure of these T cells to produce anti-tumor immune response By targeting PD-1 with antibodies that block PD-1 or its ligands, the proliferation of CD8 + T cells can be induced Therefore, in terms of cancer, PD-1 is considered to be the main inhibitor of effector T cells However, in terms of cancer cells and antigen-presenting cells, people focus on the expression of PD-1 ligands on their surfaces The expression of PD-1 ligand in tumor microenvironment is often a prerequisite for recruiting patients to participate in clinical trials involving PD-1 pathway blockade However, the patient response is not always related to the expression of PD-1 ligand, which indicates that people do not fully understand how the components of PD-1 pathway inhibit the anti-tumor immune response In addition, whether myeloid cell-specific PD-1 knockout or T-cell-specific PD-1 knockout, their role in antitumor immune response is unclear, because most studies use PD-1 blocking antibody or PD-1 gene knockout mice In a new study, researchers from Harvard Medical School in the United States revealed that PD-1 pathway plays a previously unrecognized role in lineage fate commitment and function of myeloid cells produced during tumor driven emergency myelogenesis The relevant research results were published in the Journal of science immunology on January 3, 2020, and the title of the paper was "targeted deletion of PD-1 in myeloid cells inductions antiunit or Immunology" The corresponding author of the paper is Professor vassiliki a boussiotis of Harvard Medical School Picture from science immunology, 2020, DOI: 10.1126/sciimmunologol.aay1863 Myeloid cells are produced by myeloid progenitor cells in bone marrow during tumor driven emergency myelogenesis Myeloid cells can be differentiated into myeloid suppressor cells (MDSC), monocytes / macrophages and dendritic cells, as well as granulocytes Boussiotis and his team studied how PD-1 regulates the response of myeloid progenitor cells to cancer driven emergency bone marrow production and its effect on antitumor immune response They found that myeloid progenitor cells that proliferate during cancer driven emergency myelogenesis express PD-1 and PD-L1 PD-L1 is constitutively expressed on the surface of common myeloid progenitor (CMP) and granulocyte / macrophage progenitor (GMP), while PD-1 expression is significantly increased on the surface of GMP cells produced during cancer driven emergency bone marrow generation In tumor bearing mice, PD-1 is also expressed on the surface of tumor infiltrating myeloid cells, including two major MDSC cell subsets (m-mdsc and pmn-mdsc), CD11b + F4 / 80 + macrophages (CD11b + F4 / 80 + m Φ), and CD11c + MHCII + dendritic cells (CD11c + MHCII + DC) In addition, it is also expressed on the surface of MDSC cells in patients with refractory lymphoma In PD-1 knockout mice, PD-1 signal deletion prevented GMP cell aggregation and MDSC cell production, and resulted in an increase in the number of effector monocytes with high expression of M Φ and LY6 in dendritic cells, macrophages The boussiotis team also developed mice that conditionally target the PDCD1 gene to selectively remove PD-1 from myeloid or T cells Compared with T-cell-specific PD-1 knockout, myeloid cell-specific PD-1 knockout is more effective in reducing tumor growth in a variety of tumor models At the cellular level, although PD-1 expression is preserved in T cells, PD-1 rejection of myeloid cells makes the fate of myeloid cells from MDSC to monocytes with high expression of M Φ and LY6 in dendritic cells, macrophages, induces the production of effective memory T cells (TEM) with improved functionality, and mediates the anti-tumor protection In myeloid progenitor cells lacking PD-1, growth factors that promote emergency bone marrow production, such as granulocyte colony stimulating factor (G-CSF) and granulocyte macrophage colony growth factor (GM-CSF), lead to an increase in glycolysis, pentose phosphate pathway and metabolic intermediates in the tricarboxylic acid cycle, the most prominent of which is an increase in cholesterol Since cholesterol is necessary for the differentiation of inflammatory macrophages and dendritic cells, and it can promote antigen-presenting function, these findings suggest that metabolic reprogramming and effective myeloid cell differentiation for emergency bone marrow production may be the key mechanism of PD-1 blocking mediated antitumor immune response (BIOON Com) reference: 1 Laura Strauss et al Targeted deletion of PD-1 in myeloid cells inductions antibody immunity Science immunology, 2020, DOI: 10.1126/scientific.aay1863 2 Christopher E Rudd A new perspective in cancer immunity: PD-1 on myeloid cells takes center stage in orchestrating immunity checkpoint blockade Science Immunology, 2020, doi:10.1126/sciimmunol.aaz8128.