The cross-talk of myeloid cells with T cells coordinates immune responses that regulate the balance between immune activation and tolerance. Recent progress has focused attention on metabolic regulation of coordinated innate and adaptive immune responses.

The induction of programmed death 1 (PD-1) in T cells, and its ligand, PD-L1, on myeloid cells can limit effector T cell responses and provide protection from immune-mediated tissue damage. This pathway is co-opted by tumors to promote host immune evasion.Selective deletion of PD-1 expression on myeloid bone marrow precursors and myeloid cells switches myelopoiesis to effector-like cells with enhanced antigen-presenting capacity. Ablation of PD-1 in myeloid cells causes them to engage in glycolysis-driven cholesterol metabolism(a pathway critical for progenitor differentiation), enhanced APC function and increased anti-tumor T cell immunity.

Despite important clinical benefits, immune checkpoint blockade is associated with immune-related adverse events (irAEs), that include pneumonitis and cardiovascular artery disease (CAD). IrAEs are discussed to arise from persistent immune activation and to nutrient excess.

Blockade of PD-1 in metabolically predisposed patients or patients with pre-existing inflammatory diseases might lead to excessive nutrient uptake and mitochondrial activity resulting in high levels of intracellular ROS (reactive oxygen species) and oxidized lipids. Lipid accumulation in monocytes and macrophages leads to foam cell formation, key drivers of pneumonitis and CAD. High levels of glucose/lactate or oxidized lipids activate the immunoinhibitory PD-1/PD-L1 pathway, leading to enhanced immunosuppressive activity of MDSC (myeloid-derived suppressor cells) and impaired T cell, DC and NK cell function, promoting the formation of tumor metastases.

Dear Colleagues,

Inhibitory immune checkpoints such as PD‐1/PD‐L1 normally maintain peripheral tolerance by disabling the activation and effector functions of autoreactive T‐cells and avoiding uncontrolled myeloid cell activation, have been found to be co‐opted in cancer. Monoclonal antibodies that neutralize these pathways have represented a significant step forward in incorporating immunotherapy into the fight against cancer.

Unfortunately, observations of acquired resistance and toxicity to immune checkpoint blockade occurring in a substantial proportion of patients enrolled in clinical trials have been reported. As immunotherapy is further incorporated into routine clinical practice, an increase in the number of reported cases of relapse and adverse side effects is to be expected. Therefore, experimental research to identify resistance and toxicity pathways to overcome are required.

Metabolic reprogramming of T and myeloid cells in patients with cancer and autoimmune diseases has been increasingly investigated. Of interest are the functional activities through which myeloid cells instruct T cells. Monocytes and macrophages serve as antigen-presenting cells and fine tune T cell responses. By expressing PD-1/PD-L1, they can also suppress T cell immunity, a functional aspect of importance in tumors with PD-1 or PD-L1hi tumor–associated monocytes and macrophages. Research over the last decade have shown that PD-1/PD-L1 blockade on T or myeloid cells increases glucose and lipid metabolism, metabolic networks critical for inducing efficient anti-tumor immune responses. Significantly, very recent reports show that overnutrition promotes persistent T and myeloid activation and impairs timely resolution of inflammation, resulting in immune-driven tissue damage.

Therefore, harnessing immune cell functions for immune checkpoint therapy and regenerative medicine applications requires an understanding of the metabolic networks that direct the maintenance, heterogeneity, and protective and pathological function of immune cells.

In this Special Issue, dedicated to Immuno-metabolism, we present a collection of works that provide insight into this diverse spectrum of metabolic reprogramming of myeloid and T cell activities within the host immune and tissue repair responses, and the contribution of chronic inflammation and metabolic syndrome to resistance and toxicity pathways to immuno-checkpoint therapy.

Dr. Laura Strauss
Guest Editor

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• lipid and glucose metabolism
• oxidized lipids
• metabolic reprogramming
• monocytes/macrophages
• MDSC
• bone marrow progenitors
• T cells
• PD-1/PD-L1
• tissue homeostasis
• fibrosis
• overnutrition
• irAEs
• chronic inflammation.