Therapeutic targeting of trained immunity

Abstract

Immunotherapy is revolutionizing the treatment of diseases in which dysregulated immune responses have an important role. However, most of the immunotherapy strategies currently being developed engage the adaptive immune system. In the past decade, both myeloid (monocytes, macrophages and dendritic cells) and lymphoid (natural killer cells and innate lymphoid cells) cell populations of the innate immune system have been shown to display long-term changes in their functional programme through metabolic and epigenetic programming. Such reprogramming causes these cells to be either hyperresponsive or hyporesponsive, resulting in a changed immune response to secondary stimuli. This de facto innate immune memory, which has been termed 'trained immunity', provides a powerful 'targeting framework' to regulate the delicate balance of immune homeostasis, priming, training and tolerance. In this Opinion article, we set out our vision of how to target innate immune cells and regulate trained immunity to achieve long-term therapeutic benefits in a range of immune-related diseases. These include conditions characterized by excessive trained immunity, such as inflammatory and autoimmune disorders, allergies and cardiovascular disease and conditions driven by defective trained immunity, such as cancer and certain infections.

Fig. 1 |. Excessive and defective trained immunity in disease.

Conditions that are characterized by excessive trained immunity, including organ rejection, cardiovascular diseases and autoimmune diseases, and conditions in which defective trained immunity facilitates disease progression, such as cancer, represent two sides of the ‘same immunological coin’. Therefore, regulating trained immunity can be developed into a therapeutic avenue to treat such diseases. Therapeutically engaging trained immunity is compelling as it allows for durable responses, yet these are reversible. GvHD, graft versus host disease.

Fig. 2 |. Processes that control trained immunity, at the epigenetic, cellular and systems level.

Trained immunity is regulated by metabolic and epigenetic rewiring of innate immune cells. Although the exact histone modifications that occur in this rewiring are still the topic of intense investigations, the histone mark H3K4 trimethylation (H3K4me3) has been identified to correlate well with Bacille Calmette-Guérin (BCG)-induced and β-glucan-induced trained immunity. Whereas naive cells (green) respond relatively mildly to an insult, ‘trained’ cells (red) respond much more strongly to the same stimulus. The fungal pathogen-associated molecular pattern (PAMP) β-glucan, bacterial PAMP BCG and other molecular structures such as peptidoglycans and their derivatives have been identified to induce trained immunity. At the cellular level, myeloid cells that are exposed to the aforementioned PAMPs undergo epigenetic and metabolic rewiring, resulting in a stronger response upon restimulation. At a systems level, involving the full haematopoietic system in mammals, bone marrow progenitors can be stimulated to produce ‘trained’ myeloid cells for a prolonged period of time, thereby providing a compelling framework for durable therapeutic interventions. GM-CSF, granulocyte-macrophage colony-stimulating factor; H3K4me1, H3K4 monomethylation; IL, interleukin.

Fig. 3 |. Trained-immunity-regulating pathways.

Changes in glucose (purple pathway) or lipid (light blue pathway) metabolism may both lead to epigenetic modifications underlying cytokine expression. Metabolic switching towards aerobic glycolysis results in epigenetic modifications in innate immune cells and enhanced secretion of pro-inflammatory cytokines. The role of glycolysis as a pathway that drives the induction of trained immunity in monocytes is demonstrated by the blockade of glycolysis by incubation of cells with 2-deoxy-d-giucose (2-DG). The pharmacological modulation of rate-limiting glycolysis enzymes with 2-DG inhibits the generation of histone marks underlying trained immunity. Oxidized low-density lipoprotein (oxLDL) induces trained immunity (light blue pathway). OxLDL-dependent activation of NLRP3 leads to trained immunity. CD36 internalization, cholesterol crystal formation and NLRP3 activation can be inhibited by cytochalasin D (CYTOD), methyl-β-cyclodextrin (MβCD) and Z-VAD-FMK, respectively. The cholesterol synthesis pathway (yellow), through mevalonate, is linked to the induction of trained immunity. Inhibition of cholesterol synthesis with fluvastatin downregulates H3K4 trimethylation (H3K4me3) and prevents the induction of trained immunity and the production of pro-inflammatory cytokines. Mevalonate induces trained immunity by epigenetic reprograming of macrophages, which is prevented by inhibitors of enzymes downstream of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase (HMG-CoAi). In trained immunity, the most widely studied pattern recognition receptors (PRRs) are the C-type lectin receptor dectin 1 (REF.) (dark blue pathway), which is involved in antifungal immunity and can be activated by β-glucan, and nucleotide-binding oligomerization domain-containing protein 2 (NOD2; green pathway), which recognizes bacterial molecules, such as muramyl dipeptide (MDP). Dectin 1-mediated macrophage activation induces specific epigenetic marks that lead to trained immunity. This pathway is inhibited by metformin, rapamycin and ascorbate, which target AKT, mechanistic target of rapamycin (mTOR) and hypoxia-inducible factor 1α (HIFlα), respectively. Peptidoglycan (PepG) is a pathogen-associated molecular pattern (PAMP) that synergizes with endotoxin to cause the release of inflammatory cytokines^,. MDP is the smallest PepG-derived molecular structure that can engage NOD2 (REF.). NOD2 activation and signalling through nuclear factor (NF)-κB stimulates epigenetic rewiring of macrophages and induces trained immunity. This activation of macrophages is inhibited by butyrate, which prevents histone acetylation. Finally, certain cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), can induce trained immunity, resulting in increased tumour necrosis factor (TNF) production upon subsequent lipopolysaccharide (LPS) stimulation. This process is dependent on MAPKs, ERK1 and ERK2 (REF.). H3K18ac, H3K18 acetylation; H3K27ac, H3K27 acetylation; HATi, histone acetyl transferase inhibitor; HDACi, histone deacetylase inhibitor; HMTi, histone methyltransferase inhibitor; IL, interleukin.

Fig. 4 |. Molecular structures that induce or inhibit trained immunity.

a | Peptidoglycans, molecular derivatives of peptidoglycans, β-glucans and small molecules that promote trained immunity. b | Examples of small-molecule inhibitors of metabolic and epigenetic pathways that regulate trained immunity.

Fig. 5 |. Regulating trained immunity with nanotechnology.

Long-term therapeutic benefits can theoretically be achieved by the intravenous administration of nanomaterials that engage myeloid cells and their stem and progenitor cells in the bone marrow. Intravenously administrable nanomaterials (yellow circles) typically accumulate in the liver and spleen but can be designed to exhibit bone marrow proclivity. Induction of trained immunity can be prevented by functionalizing these nanomaterials with molecular structures that inhibit epigenetic and metabolic pathways that regulate trained immunity (green circles). The resulting ‘green’ cells have an alternatively activated phenotype. Conversely, by incorporating molecular structures derived from PAMPs that activate dectin 1 or nucleotide-binding oligomerization domain-containing protein 2 (NOD2), nanomaterials (red circles) can be applied to promote trained immunity. These ‘red’ cells have an inflammatory phenotype. Systemically inhibiting trained immunity using this nanotechnology-based approach may be employed to treat a variety of conditions, ranging from cardiovascular disease and its clinical consequences myocardial infarction and stroke to autoimmune disorders. Therapeutically inducing trained immunity may find use in overcoming immunoparalysis in sepsis and infections and in treating cancers.

Fig. 6 |. Combining therapeutically induced and inhibited trained immunity with adaptive immunity-regulating agents.

a | Antigen-presenting cells can induce immune tolerance by targeted suppression of trained immunity through inhibition of the mechanistic target of rapamycin (mTOR) pathway with a nanobiologic, resulting in the expansion of regulatory T (T_reg) cells. These T_reg cells maintain tolerance to self-antigens, prevent autoimmune disease and promote allograft acceptance. This process can be amplified by synergistically blocking the interaction between CD40 and tumour necrosis factor receptor-associated factor 6 (TRAF6) in monocytes and macrophages, which blunts CD40 ligand-dependent T cell activation. b | Impaired antitumour immunity is caused by immunosuppressive cell infiltration and macrophages that are programmed to drive immune suppression, leading to cytotoxic T cell exclusion. The induction of trained immunity results in enhanced ‘trained’ monocyte numbers that differentiate into antitumour macrophages and facilitate T cell activation. HDL, high-density lipoprotein; MDSC, myeloid-derived suppressor cell; mTORi-HDL, HDL nanoparticle incorporating an mTOR inhibitor; TAM, tumour-associated macrophage; TRAF6i-HDL, HDL nanoparticle incorporating a TRAF6 inhibitor.