Targeted deletion of PD-1 in myeloid cells induces anti-tumor immunity

• Published in: Science immunology 2020-01, Vol.5 (43)
• Main Authors: Strauss, Laura, Mahmoud, Mohamed A.A., Weaver, Jessica D., Tijaro-Ovalle, Natalia M., Christofides, Anthos, Wang, Qi, Pal, Rinku, Yuan, Min, Asara, John, Patsoukis, Nikolaos, Boussiotis, Vassiliki A.
• Format: Article
• Language: English
• ISSN: 2470-9468
• DOI: 10.1126/sciimmunol.aay1863

PD-1, a T cell checkpoint receptor and target of cancer immunotherapy, is also expressed on myeloid cells. The role of myeloid-specific vs. T cell-specific PD-1 ablation on anti-tumor 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-1 f/fLysMcre ) or T cell-specific (PD-1 f/fCD4cre ) targeting of Pdcd1 gene. Compared to T cell-specific PD-1 ablation, myeloid cell-specific PD-1 ablation more effectively decreased tumor growth. We found that granulocyte/macrophage progenitors (GMP), which accumulate during cancer-driven emergency myelopoiesis and give rise to myeloid-derived suppressor cells (MDSC), express PD-1. In tumor-bearing PD-1 f/fLysMcre but not PD-1 f/fCD4cre mice, accumulation of GMP and MDSC was prevented, while systemic output of effector myeloid cells was increased. Myeloid cell-specific PD-1 ablation induced an increase of T effector memory (T EM ) cells with improved functionality, and mediated anti-tumor 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. As 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 anti-tumor immunity mediated by PD-1 blockade. PD-1 ablation regulates metabolism-driven lineage fate commitment of myeloid progenitors and differentiation of effector myeloid cells