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

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.

Analyzing One Cell at a TIME: Analysis of Myeloid Cell Contributions in the Tumor Immune Microenvironment

“…Interestingly, PD-1 deficient myeloid progenitors also had increased cholesterol synthesis which is required for the differentiation of inflammatory macrophages. Additionally, PD-1 ablation on myeloid cells decreased tumor growth more effectively than T-cell specific PD-1 ablation in a murine fibrosarcoma and melanoma models ( 109 ). Cumulatively, PD-1/PD-L1 blockade or ablation on myeloid cells promotes phagocytosis in macrophages, reprogramming of myeloid progenitors and even furthers myeloid differentiation via metabolic pathways.…”

Revisiting the PD-1 pathway

“…Recent studies revealed that the PD-1:PD-L1 axis is activated in CMP and GMP myeloid progenitors that accumulate during cancer-driven emergency myelopoiesis ( 126 ). This is an early event that occurs during the growth of cancer cells and occurs even before the tumor obtains a detectable size.…”

“…Thus, antitumor T cell responses are guided by the consequences of PD-1 signaling in myeloid cells, and PD-1 ablation in T cells, alone, might not be sufficient to promote sustained antitumor function. Instead, it might rather work against antitumor immunity by promoting the accumulation of terminally differentiated T effector cells that promote the generation of MDSCs ( 126 ). Consistent with these findings, triggering PD-1 on monocytes from patients with chronic lymphocytic leukemia hampers glycolysis, phagocytosis, and Bruton’s tyrosine kinase signaling, whereas disrupting PD-1/PD-L1 signaling reverses these immune metabolic dysfunctions ( 124 ).…”

Connections between Metabolism and Epigenetic Modification in MDSCs

“…Thus, cholesterol production in MDSCs can be inhibited in the presence of PD-1. Therefore, the metabolic reprogramming of emergent myelogenesis and effector myeloid cell differentiation may be the key mechanism of anti-tumor immunity mediated by PD-1 blocking [ 55 ]. In addition, liver X receptors (LXRα and LXRβ) are transcription factors of the nuclear hormone receptor family.…”

“…In a hypoxic environment, MDSCs inhibit T cell metabolism by hoarding key amino acids [ 55 ]. MDSCs deplete l -cysteine by depletion and sequestration of l -cysteine, resulting in the stagnation of T cell proliferation [ 2 ].…”