The Sweet Surrender: How Myeloid Cell Metabolic Plasticity Shapes the Tumor Microenvironment

Immune cells are one of the most versatile cell types, as they can tailor their metabolic activity according to their required function. In response to diverse environmental cues, immune cells undergo metabolic reprogramming to support their differentiation, proliferation and pro-inflammatory effector functions. To meet a dramatic surge in energetic demand, immune cells rewire their metabolism to utilize aerobic glycolysis. This preferential use of glycolysis even under aerobic conditions is well established in tumor cells, and is known as the “Warburg effect.” Tumor cells avidly use glucose for aerobic glycolysis, thereby creating a nutrient-starved microenvironment, outcompeting T cells for glucose, and directly inhibiting T-cell anti-tumoral effector function. Given that both immune and tumor cells use similar modes of metabolism in the tumor stroma, it is imperative to identify a therapeutic window in which immune-cell and tumor-cell glycolysis can be specifically targeted. In this review, we focus on the Warburg metabolism as well as other metabolic pathways of myeloid cells, which comprise a notable niche in the tumor environment and promote the growth and metastasis of malignant tumors. We examine how differential immune-cell activation triggers metabolic fate, and detail how this forbidding microenvironment succeeds in shutting down the vigorous anti-tumoral response. Finally, we highlight emerging therapeutic concepts that aim to target immune-cell metabolism. Improving our understanding of immunometabolism and immune-cell commitment to specific metabolic fates will help identify alternative therapeutic approaches to battle this intractable disease

Metabolic reprogramming of tumor-infiltrating myeloid cells conveys protection against pancreatic ductal adenocarcinoma

Myriad mechanisms of immune evasion contribute to therapeutic resistance of pancreatic cancer and poor survival. While it is well established that tumor cells exhibit the Warburg effect for energy production, the contribution of myeloid cell metabolism to disease progression is unknown. In this study, we highlight the importance of immunometabolism, specifically demonstrating that the metabolic signature of an immune cell can instruct downstream effector function. Utilizing a combination of an in vitro model of tumor-conditioned human macrophages, an orthotopic pancreatic ductal adenocarcinoma mouse model and patient-derived specimens, we define a pronounced glycolytic signature in tumor-infiltrating myeloid cells that confer them a pro-tumoral phenotype. Inhibiting glycolysis with 2-deoxyglucose, macrophage-specific deletion of glucose transporter 1 or neutrophil-specific deletion of hypoxia-inducible factor 1-alpha independently ameliorates disease. Our results indicate that glycolysis is a key control point in the immunological reprogramming of tumor-infiltrating myeloid cells, and highlight the therapeutic potential of targeting this metabolic pathway to improve patient outcome.Doctor of Philosoph

Targeting immune cells for cancer therapy

Recent years have seen a renaissance in the research linking inflammation and cancer with immune cells playing a central role in smouldering inflammation in the tumor microenvironment. Diverse immune cell types infiltrate the tumor microenvironment, and the dynamic tumor-immune cell interplay gives rise to a rich milieu of cytokines and growth factors. Fundamentally, this intricate cross-talk creates the conducive condition for tumor cell proliferation, survival and metastasis. Interestingly, the prominent impact of immune cells is expounded in their contrary pro-tumoral role, as well as their potential anti-cancer cellular weaponry. The latter is known as immunotherapy, a concept born out of evidence that tumors are susceptible to immune defence and that by manipulating the immune system, tumor growth can be successfully restrained. Naturally, a deeper understanding of the multifaceted roles of various immune cell types thus contributes toward developing innovative anti-cancer strategies. Therefore, in this review we first outline the roles played by the major immune cell types, such as macrophages, neutrophils, natural killer cells, T cells and B cells. We then explain the recently-explored strategies of immunomodulation and discuss some important approaches via an immunology perspective.Agency for Science, Technology and Research (A*STAR)Published versio

Modulating macrophage phenotype by sustained microRNA delivery improves host‐implant integration

Biomedical implant failure due to the host's response remains a challenging problem. In particular, the formation of the fibrous capsule is a common barrier for the normal function of implants. Currently, there is mounting evidence indicating that the polarization state of macrophages plays an important role in effecting the foreign body reaction (FBR). This opens up a potential avenue for improving host‐implant integration. Here, electrospun poly(caprolactone‐co ‐ethyl ethylene phosphate) nanofiber scaffolds are utilized to deliver microRNAs (miRs) to induce macrophage polarization and modulate FBR. Specifically, C57BL/6 mice that are treated with M2‐inducing miRs, Let‐7c and miR‐124, display relatively thinner fibrous capsule formation around the scaffolds at both Week 2 and 4, as compared to treatment with M1‐inducing miR, Anti‐Let‐7c. Histological analysis shows that the density of blood vessels in the scaffolds are the highest in miR‐124 treatment group, followed by Anti‐Let‐7c and Let‐7c treatment groups. Based on immunohistochemical quantifications, these miR‐encapsulated nanofiber scaffolds are useful for localized and sustained delivery of functional miRs and are able to modulate macrophage polarization during the first 2 weeks of implantation to result in significant alteration in host‐implant integration at longer time points.NRF (Natl Research Foundation, S’pore)MOE (Min. of Education, S’pore)NMRC (Natl Medical Research Council, S’pore)MOH (Min. of Health, S’pore)Accepted versio

Conditional Knockout of Hypoxia-Inducible Factor 1-Alpha in Tumor-Infiltrating Neutrophils Protects against Pancreatic Ductal Adenocarcinoma

Large numbers of neutrophils infiltrate tumors and comprise a notable component of the inflammatory tumor microenvironment. While it is established that tumor cells exhibit the Warburg effect for energy production, the contribution of the neutrophil metabolic state to tumorigenesis is unknown. Here, we investigated whether neutrophil infiltration and metabolic status promotes tumor progression in an orthotopic mouse model of pancreatic ductal adenocarcinoma (PDAC). We observed a large increase in the proportion of neutrophils in the blood and tumor upon orthotopic transplantation. Intriguingly, these tumor-infiltrating neutrophils up-regulated glycolytic factors and hypoxia-inducible factor 1-alpha (HIF-1α) expression compared to neutrophils from the bone marrow and blood of the same mouse. This enhanced glycolytic signature was also observed in human PDAC tissue samples. Strikingly, neutrophil-specific deletion of HIF-1α (HIF-1αΔNφ) significantly reduced tumor burden and improved overall survival in orthotopic transplanted mice, by converting the pro-tumorigenic neutrophil phenotype to an anti-tumorigenic phenotype. This outcome was associated with elevated reactive oxygen species production and activated natural killer cells and CD8+ cytotoxic T cells compared to littermate control mice. These data suggest a role for HIF-1α in neutrophil metabolism, which could be exploited as a target for metabolic modulation in cancer

Synthetic Nanoparticles That Promote Tumor Necrosis Factor Receptor 2 Expressing Regulatory T Cells in the Lung and Resistance to Allergic Airways Inflammation

Synthetic glycine coated 50 nm polystyrene nanoparticles (NP) (PS50G), unlike ambient NP, do not promote pulmonary inflammation, but instead, render lungs resistant to the development of allergic airway inflammation. In this study, we show that PS50G modulate the frequency and phenotype of regulatory T cells (Treg) in the lung, specifically increasing the proportion of tumor necrosis factor 2 (TNFR2) expressing Treg. Mice pre-exposed to PS50G, which were sensitized and then challenged with an allergen a month later, preferentially expanded TNFR2+Foxp3+ Treg, which further expressed enhanced levels of latency associated peptide and cytotoxic T-lymphocyte associated molecule-4. Moreover, PS50G-induced CD103+ dendritic cell activation in the lung was associated with the proliferative expansion of TNFR2+Foxp3+ Treg. These findings provide the first evidence that engineered NP can promote the selective expansion of maximally suppressing TNFR2+Foxp3+ Treg and further suggest a novel mechanism by which NP may promote healthy lung homeostasis

Developmental Analysis of Bone Marrow Neutrophils Reveals Populations Specialized in Expansion, Trafficking, and Effector Functions

Neutrophils are specialized innate cells that require constant replenishment from proliferative bone marrow (BM) precursors as a result of their short half-life. Although it is established that neutrophils are derived from the granulocyte-macrophage progenitor (GMP), the differentiation pathways from GMP to functional mature neutrophils are poorly defined. Using mass cytometry (CyTOF) and cell-cycle-based analysis, we identified three neutrophil subsets within the BM: a committed proliferative neutrophil precursor (preNeu) which differentiates into non-proliferating immature neutrophils and mature neutrophils. Transcriptomic profiling and functional analysis revealed that preNeu require the C/EBPε transcription factor for their generation from the GMP, and their proliferative program is substituted by a gain of migratory and effector function as they mature. preNeus expand under microbial and tumoral stress, and immature neutrophils are recruited to the periphery of tumor-bearing mice. In summary, our study identifies specialized BM granulocytic populations that ensure supply under homeostasis and stress responses.We thank all members of L.G.N laboratory, the SIgN (Singapore Immunology Network) flow-cytometry team, the SIgN functional genomics team for their assistance with transcriptomics, and the SIgN mouse core facility for their technical help and support. This research was funded by SIgN core funding, A*STAR (Agency for Science, Technology and Research), Singapore.S