Research ArticleTUMOR IMMUNOLOGY

Targeted deletion of PD-1 in myeloid cells induces antitumor immunity

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Science Immunology  03 Jan 2020:
Vol. 5, Issue 43, eaay1863
DOI: 10.1126/sciimmunol.aay1863

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A twist in the PD-1 tale

Immunotherapies targeting programmed cell death protein 1 (PD-1) that can reverse T cell exhaustion have revolutionized the treatment of cancer. Here, by generating Pdcd1 floxed mice and conditionally deleting PD-1 in T cells or in myeloid cells, Strauss et al. have uncovered a previously unappreciated role for PD-1 expressed on myeloid cells in dampening antitumor immunity. They found that selective ablation of PD-1 in myeloid cells was just as effective at limiting tumor growth as global deletion of PD-1 and have documented the importance of PD-1 in regulating the development and functions of myeloid cells. Although the study does not question the role of PD-1 in T cell exhaustion, the results call for a rethink of how PD-1–centric therapies work.

Abstract

PD-1, a T cell checkpoint receptor and target of cancer immunotherapy, is also expressed on myeloid cells. The role of myeloid-specific versus T cell–specific PD-1 ablation on antitumor immunity has remained unclear because most studies have used either PD-1–blocking antibodies or complete PD-1 KO mice. We generated a conditional allele, which allowed myeloid-specific (PD-1f/fLysMcre) or T cell–specific (PD-1f/fCD4cre) targeting of Pdcd1 gene. Compared with T cell–specific PD-1 ablation, myeloid cell–specific PD-1 ablation more effectively decreased tumor growth. We found that granulocyte/macrophage progenitors (GMPs), which accumulate during cancer-driven emergency myelopoiesis and give rise to myeloid-derived suppressor cells (MDSCs), express PD-1. In tumor-bearing PD-1f/fLysMcre but not PD-1f/fCD4cre mice, accumulation of GMP and MDSC was prevented, whereas systemic output of effector myeloid cells was increased. Myeloid cell–specific PD-1 ablation induced an increase of T effector memory cells with improved functionality and mediated antitumor protection despite preserved PD-1 expression in T cells. In PD-1–deficient myeloid progenitors, growth factors driving emergency myelopoiesis induced increased metabolic intermediates of glycolysis, pentose phosphate pathway, and TCA cycle but, most prominently, elevated cholesterol. Because cholesterol is required for differentiation of inflammatory macrophages and DC and promotes antigen-presenting function, our findings indicate that metabolic reprogramming of emergency myelopoiesis and differentiation of effector myeloid cells might be a key mechanism of antitumor immunity mediated by PD-1 blockade.

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