Macrophage-based Cell Strategies: A Novel Approach in Immunotherapy.

Immune modulation is the prerequisite for the effective therapy of both infections and cancer. A variety of cell-based hematopoietic products have been used in therapies for over 50 years, including platelets, granulocytes, bone marrow cells and most recently engineered anti-cancer targeted T-lymphocytes. In particular, adoptive transfer of immune cells has been established as a promising approach especially for the treatment of cancer. Although most research to date has focused on the development of cellular therapies from lymphocyte-derived cells, their efficacy in the treatment of solid tumors as well as infections remains elusive. Lately, the development of cell therapies was extended to macrophages. Using cells of the myeloid lineage—such as monocytes and macrophages—offers multiple advantages, including the opportunity to boost endogenous immunity via antigen presentation and achieve improved tumor- and infection site-homing, making them a unique avenue for infection and antitumor cell therapy development.[1]

Macrophages are potent immune effector cells distributed in all organs where they serve critical functions in maintaining homeostasis in adult tissues. Tissue-specific macrophages are involved in phagocytosis of dead and infected cells, maintain T-cell tolerance in healthy tissues and initiate immune responses upon bacterial infection. Macrophages act as tissue auxiliary cells that carry out surveillance for tissue integrity, maintain tissue turnover and recruit the immune system to overcome larger tissue damage. Importantly, macrophages display enormous functional plasticity based on their ability to respond to stimuli and adopt distinct phenotypes and specific functionality in the surrounding microenvironment. The exceptional plasticity of tissue macrophages, combined with the centrality of a variety of subtypes in the control of tissue homeostasis and activation of immune responses to outside and internal insults, make macrophages ideal building blocks for a multitude of future tissue replacement therapies.[1]

So far, the application of macrophages has focused on the following directions: (1) use of generated or educated macrophages to repopulate macrophage population and exploit their innate properties or shift their phenotypic balance, (2) use of macrophages as delivery vehicles for small molecules, plasmid DNA, and other therapeutics, and (3) use of genetically engineered macrophages to augment existing macrophage behaviors or endow new functionalities for therapeutic purposes.[1]

Although enhancing the immune system by cell-based approaches has revolutionized cancer immunotherapies in past years, the potential of macrophage-based cell therapies enhancing the immune system to combat infections has remained under-investigated.

Respiratory infections are a major cause of morbidity and mortality among immunodeficient or immunocompromised patients. In this patient population, innate and humoral immunities are compromised. In particular, myeloid cell dysfunction is common and predisposes immunodeficient patients to severe bacterial infections. Pulmonary infections by Staphylococcus aureus represent a major threat to immunocompromised patients, often aggravated by the development of antibiotic-resistant strains.

Considering the unmet clinical need and the high morbidity and mortality of S. aureus in immunodeficient patients, Hashtchin et al[2] recently explored the applicability of a macrophage-based immunotherapy against pulmonary S. aureus infections in immunodeficient condition. Using a scalable production platform, the authors generated a highly pure population of macrophages derived from human-induced pluripotent stem cells (iPSCs). These macrophages were hallmarked by the expression of typical macrophage markers (CD14, CD68, CD64), elevated phagocytic activity, and efficient intracellular clearing ability of S. aureus. As mouse model of immunodeficiency, the authors used mice lacking murine interleukin (IL)-3 and granulocyte-macrophage colony-stimulating factor production, which leads to T, B, and natural killer cells deficiency and defective myeloid cell development.

While immunodeficient mice infected via intratracheal instillation of S. aureus developed extensive pulmonary infection, infected immunodeficient mice treated with iPSC-derived macrophages showed sign of a significantly less severe infection, with reduced pulmonary bacterial load, decreased monocyte and granulocyte infiltration, and overall less edema and tissue damage (Figure 1).[2] Interestingly, the authors compared iPSC-derived versus peripheral blood monocyte-derived macrophages as potential source of cell immunotherapy. A significantly stronger antimicrobial response was provided by iPSC-derived macrophages, as suggested by the higher secretion of IL-6, a crucial pro-inflammatory cytokine driver of immunity against S. aureus. Transcriptomic changes in macrophages 2 hours post S. aureus infection were more than 10-fold higher in iPSC-derived macrophages than in peripheral blood monocyte-derived macrophages. Upregulated genes in iPSC-derived macrophages included several pro-inflammatory chemokines and cytokines (eg, C-C Motif Chemokine Ligand 3/5/16/20, C-X-C Motif Chemokine Ligand 1/2/3/8, IL-12, IL-36, IL-23A, tumor necrosis factor, IL-1, and IL-6), as well as the inflammatory response-related transcription factor NF-kB. While 24 hours post-infection iPSC-derived macrophages showed a gene expression profile more similar to uninfected macrophages, peripheral blood monocyte-derived macrophages displayed a continuously elevated inflammatory gene expression, comparable to 2 hours post-infection. The sustained upregulation of pro-inflammatory cytokines and chemokines led to a persistent pro-inflammatory status in peripheral blood monocyte-derived macrophages, which, by contrast, was almost completely rescued in iPSC-derived macrophages 24 hours after the infection. Overall, these findings highlighted the superiority of certain sources of cells to generate therapeutic macrophages with more effective antimicrobial response.

Figure 1.

Macrophage-based therapy in pulmonary infections. Macrophages derived from human iPSCs were exploited as cell therapy to repopulate the defective population of alveolar macrophages in immunodeficient mice exposed to Staphylococcus aureus infection. iPSC-derived macrophages displayed a strong antimicrobial response that helped to effectively reduce bacterial load and tissue damage in infected immunodeficient animals. iPSC = induced pluripotent stem cell.

In line with this work, previous studies showed that in animal models of pulmonary alveolar proteinosis, which display a defect in alveolar macrophage production, adoptively transferred wild-type alveolar macrophages assume lung-specific function and very long persistence and result in significantly reduced alveolar proteinosis, normalized lung densities and improved lung function. Moreover, effort has been made in attempting to express therapeutic proteins through gene correction in hematopoietic stem/progenitor cell-derived macrophages used for pulmonary cell therapy[3,4] or change the functional behavior of adoptively transferred macrophages.[5]

Overall, recent research demonstrated the significance of macrophage-directed therapies in addressing a broad range of inflammatory diseases, which include cancer and autoimmune disorders and extend to pulmonary infectious diseases. This study highlights adoptive transfer of iPSC-derived macrophages as a promising approach to enhance a debilitated immunity and combat S. aureus infections. Given the important role of macrophages as the first line of cellular host defense, immunotherapy approach can complement antibiotic therapy and offer novel treatment options for immunocompromised patients.

DISCLOSURES

The author has no conflicts of interest to disclose.