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.

Targeting Glycolysis in Macrophages Confers Protection Against Pancreatic Ductal Adenocarcinoma.

Inflammation in the tumor microenvironment has been shown to promote disease progression in pancreatic ductal adenocarcinoma (PDAC); however, the role of macrophage metabolism in promoting inflammation is unclear. Using an orthotopic mouse model of PDAC, we demonstrate that macrophages from tumor-bearing mice exhibit elevated glycolysis. Macrophage-specific deletion of Glucose Transporter 1 (GLUT1) significantly reduced tumor burden, which was accompanied by increased Natural Killer and CD8+ T cell activity and suppression of the NLRP3-IL1ß inflammasome axis. Administration of mice with a GLUT1-specific inhibitor reduced tumor burden, comparable with gemcitabine, the current standard-of-care. In addition, we observe that intra-tumoral macrophages from human PDAC patients exhibit a pronounced glycolytic signature, which reliably predicts poor survival. Our data support a key role for macrophage metabolism in tumor immunity, which could be exploited to improve patient outcomes.

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.

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.

Pathogenic CD8+ T cells in experimental cerebral malaria.

Cerebral malaria (CM) is one the major complications occurring during malaria infection. The mechanisms leading to this syndrome are still not completely understood. Although it is clear that parasite sequestration is the key initiation factor, the downstream pathological processes are still highly debated. The experimental cerebral malaria (ECM) model, in which susceptible mice are infected with Plasmodium berghei ANKA, has led to the identification of CD8(+) T cells as the major mediator of ECM death. In this review, we discuss the recent advances and future developments in the understanding of the role of CD8(+) T cells in CM.