Single cell transcriptomic analyses reveal diverse and dynamic changes of distinct populations of lung interstitial macrophages in hypoxia-induced pulmonary hypertension.

Introduction: Hypoxia is a common pathological driver contributing to various forms of pulmonary vascular diseases leading to pulmonary hypertension (PH). Pulmonary interstitial macrophages (IMs) play pivotal roles in immune and vascular dysfunction, leading to inflammation, abnormal remodeling, and fibrosis in PH. However, IMs' response to hypoxia and their role in PH progression remain largely unknown. We utilized a murine model of hypoxia-induced PH to investigate the repertoire and functional profiles of IMs in response to acute and prolonged hypoxia, aiming to elucidate their contributions to PH development. Methods: We conducted single-cell transcriptomic analyses to characterize the repertoire and functional profiles of murine pulmonary IMs following exposure to hypobaric hypoxia for varying durations (0, 1, 3, 7, and 21 days). Hallmark pathways from the mouse Molecular Signatures Database were utilized to characterize the molecular function of the IM subpopulation in response to hypoxia. Results: Our analysis revealed an early acute inflammatory phase during acute hypoxia exposure (Days 1-3), which was resolved by Day 7, followed by a pro-remodeling phase during prolonged hypoxia (Days 7-21). These phases were marked by distinct subpopulations of IMs: MHCIIhiCCR2+EAR2+ cells characterized the acute inflammatory phase, while TLF+VCAM1hi cells dominated the pro-remodeling phase. The acute inflammatory phase exhibited enrichment in interferon-gamma, IL-2, and IL-6 pathways, while the pro-remodeling phase showed dysregulated chemokine production, hemoglobin clearance, and tissue repair profiles, along with activation of distinct complement pathways. Discussion: Our findings demonstrate the existence of distinct populations of pulmonary interstitial macrophages corresponding to acute and prolonged hypoxia exposure, pivotal in regulating the inflammatory and remodeling phases of PH pathogenesis. This understanding offers potential avenues for targeted interventions, tailored to specific populations and distinct phases of the disease. Moreover, further identification of triggers for pro-remodeling IMs holds promise in unveiling novel therapeutic strategies for pulmonary hypertension.

Crosstalk between hypoxia-induced pyroptosis and immune escape in cancer: From mechanisms to therapy.

Pyroptosis can be triggered through both canonical and non-canonical inflammasome pathways, involving the cleavage of gasdermin (GSDM) protein family members, like GSDMD and GSDME. The impact of pyroptosis on tumors is nuanced, because its role in regulating cancer progression and anti-tumor immunity may vary depending on the tumor type, stage, location, and immune status. However, pyroptosis cannot be simply categorized as promoting or inhibiting tumors based solely on whether it is acute or chronic in nature. The interplay between pyroptosis and cancer is intricate, with some evidence suggesting that chronic pyroptosis may facilitate tumor growth, while the acute induction of pyroptosis could stimulate anti-cancer immune responses. Tumor hypoxia activates hypoxia inducible factor (HIF) signaling to modulate pyroptosis and immune checkpoint expression. Targeting this hypoxia-pyroptosis-immune escape axis could be a promising therapeutic strategy. This review highlights the complex crosstalk between hypoxia, pyroptosis, and immune evasion in the TME.

Climate change can impair bacterial pathogen defences in sablefish via hypoxia-mediated effects on adaptive immunity.

Low-oxygen levels (hypoxia) in aquatic habitats are becoming more common because of global warming and eutrophication. However, the effects on the health/disease status of fishes, the world's largest group of vertebrates, are unclear. Therefore, we assessed how long-term hypoxia affected the immune function of sablefish, an ecologically and economically important North Pacific species, including the response to a formalin-killed Aeromonas salmonicida bacterin. Sablefish were held at normoxia or hypoxia (100% or 40% air saturated seawater, respectively) for 6-16 weeks, while we measured a diverse array of immunological traits. Given that the sablefish is a non-model organism, this involved the development of a species-specific methodological toolbox comprised of qPCR primers for 16 key immune genes, assays for blood antibacterial defences, the assessment of blood immunoglobulin (IgM) levels with ELISA, and flow cytometry and confocal microscopy techniques. We show that innate immune parameters were typically elevated in response to the bacterial antigens, but were not substantially affected by hypoxia. In contrast, hypoxia completely prevented the ∼1.5-fold increase in blood IgM level that was observed under normoxic conditions following bacterin exposure, implying a serious impairment of adaptive immunity. Since the sablefish is naturally hypoxia tolerant, our results demonstrate that climate change-related deoxygenation may be a serious threat to the immune competency of fishes.

PSGL-1: a novel immune checkpoint driving T-cell dysfunction in obstructive sleep apnea.

Introduction: Although higher incidence of cancer represents a major burden for obstructive sleep apnea (OSA) patients, the molecular pathways driving this association are not completely understood. Recently, the adhesion receptor P-selectin glycoprotein-1 (PSGL 1) has been identified as a novel immune checkpoint, which are recognized major hallmarks in several types of cancer and have revolutionized cancer therapy. Methods: The expression of PSGL-1 and its ligands VISTA and SIGLEC-5 was assessed in the leucocytes of OSA patients and control subjects exploring the role of intermittent hypoxia (IH) using in vitro models. In addition, PSGL-1 impact on T-cells function was evaluated by ex vivo models. Results: Data showed PSGL-1 expression is upregulated in the T-lymphocytes from patients with severe OSA, indicating a relevant role of hypoxemia mediated by intermittent hypoxia. Besides, results suggest an inhibitory role of PSGL-1 on T-cell proliferation capacity. Finally, the expression of SIGLEC-5 but not VISTA was increased in monocytes from OSA patients, suggesting a regulatory role of intermittent hypoxia. Discussion: In conclusion, PSGL-1 might constitute an additional immune checkpoint leading to T-cell dysfunction in OSA patients, contributing to the disruption of immune surveillance, which might provide biological plausibility to the higher incidence and aggressiveness of several tumors in these patients.

Hypoxia Attenuates Colonic Innate Immune Response and Inhibits TLR4/NF-κB Signaling Pathway in Lipopolysaccharide-Induced Colonic Epithelial Injury Mice.

High altitude hypoxia can lead to a spectrum of gastrointestinal problems. As the first line of host immune defense, innate immune response in the intestinal mucosa plays a pivotal role in maintaining intestinal homeostasis and protecting against intestinal injury at high altitude. This study aimed to investigate the effect of hypoxia on the colonic mucosal barrier and toll-like receptor 4 (TLR4)-mediated innate immune responses in the colon. The mice were exposed to a hypobaric chamber to simulate a 5,000 m plateau environment for 7 days, and the colonic mucosa changes were recorded. At the same time, the inflammation model was established by lipopolysaccharide (LPS) to explore the effects of hypoxia on the TLR4/nuclear factor kappa B (NF-κB) signaling pathway and its downstream inflammatory factors [tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, and interferon (IFN)-γ] in the colon. We found that hypoxic exposure caused weight loss and structural disturbance of the colonic mucosa in mice. Compared with the control group, the protein levels of TLR4 [fold change (FC) = 0.75 versus FC = 0.23], MyD88 (FC = 0.80 versus FC = 0.30), TIR-domain-containing adaptor protein inducing interferon-ß (TRIF: FC = 0.89 versus FC = 0.38), and NF-κB p65 (FC = 0.75 versus FC = 0.24) in the colon of mice in the hypobaric hypoxia group were significantly decreased. LPS-induced upregulation of the TLR4/NF-κB signaling and its downstream inflammatory factors was inhibited by hypoxia. Specifically, compared with the LPS group, the protein levels of TLR4 (FC = 1.18, FC = 0.86), MyD88 (FC = 1.20, FC = 0.80), TRIF (FC = 1.20, FC = 0.86), and NF-κB p65 (FC = 1.29, FC = 0.62) and the mRNA levels of IL-1ß (FC = 7.38, FC = 5.06), IL-6 (FC = 16.06, FC = 9.22), and IFN-γ (FC = 2.01, FC = 1.16) were reduced in the hypobaric hypoxia plus LPS group. Our findings imply that hypoxia could lead to marked damage of the colonic mucosa and a reduction of TLR4-mediated colonic innate immune responses, potentially reducing host defense responses to colonic pathogens.

Targeted inhibition of the GRK2/HIF-1α pathway is an effective strategy to alleviate synovial hypoxia and inflammation.

G-protein coupled receptor (GPCR) kinases (GRKs) and hypoxia-inducible factor-1α (HIF-1α) play key roles in rheumatoid arthritis (RA). Several studies have demonstrated that HIF-1α expression is positively regulated by GRK2, suggesting its posttranscriptional effects on HIF-1α. In this study, we review the role of HIF-1α and GRK2 in RA pathophysiology, focusing on their proinflammatory roles in immune cells and fibroblast-like synoviocytes (FLS).We then introduce several drugs that inhibit GRK2 and HIF-1α, and briefly outline their molecular mechanisms. We conclude by presenting gaps in knowledge and our prospects for the pharmacological potential of targeting these proteins and the relevant downstream signaling pathways.Future research is warranted and paramount for untangling these novel and promising roles for GRK2 and HIF-1α in RA.

ISGylation directly modifies hypoxia-inducible factor-2α and enhances its polysome association.

The hypoxia-inducible factors (HIF)-1α and HIF-2α are central regulators of transcriptional programmes in settings such as development and tumour expansion. HIF-2α moonlights as a cap-dependent translation factor. We provide new insights into how the interferon-stimulated gene 15 (ISG15), a ubiquitin-like modifier, and the HIFs regulate one another in hypoxia and interferon-induced cells. We show that upon ISGylation induction and HIF-α stabilization, both HIFs promote protein ISGylates through transcriptional and/or post-transcriptional pathways. We show the first evidence of HIF-2α modification by ISG15. ISGylation induces system-level alterations to the HIF transcriptional programme and increases the cytoplasmic/nuclear fraction and translation activity of HIF-2α. This work identifies ISG15 as a regulator of hypoxic mRNA translation, which has implications for immune processes and disease progression.

Interleukin-17 governs hypoxic adaptation of injured epithelium.

Mammalian cells autonomously activate hypoxia-inducible transcription factors (HIFs) to ensure survival in low-oxygen environments. We report here that injury-induced hypoxia is insufficient to trigger HIF1α in damaged epithelium. Instead, multimodal single-cell and spatial transcriptomics analyses and functional studies reveal that retinoic acid-related orphan receptor γt+ (RORγt+) γδ T cell-derived interleukin-17A (IL-17A) is necessary and sufficient to activate HIF1α. Protein kinase B (AKT) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling proximal of IL-17 receptor C (IL-17RC) activates mammalian target of rapamycin (mTOR) and consequently HIF1α. The IL-17A-HIF1α axis drives glycolysis in wound front epithelia. Epithelial-specific loss of IL-17RC, HIF1α, or blockade of glycolysis derails repair. Our findings underscore the coupling of inflammatory, metabolic, and migratory programs to expedite epithelial healing and illuminate the immune cell-derived inputs in cellular adaptation to hypoxic stress during repair.

The Effect of Hypoxia and Hypoxia-Associated Pathways in the Regulation of Antitumor Response: Friends or Foes?

Hypoxia is an environmental stressor that is instigated by low oxygen availability. It fuels the progression of solid tumors by driving tumor plasticity, heterogeneity, stemness and genomic instability. Hypoxia metabolically reprograms the tumor microenvironment (TME), adding insult to injury to the acidic, nutrient deprived and poorly vascularized conditions that act to dampen immune cell function. Through its impact on key cancer hallmarks and by creating a physical barrier conducive to tumor survival, hypoxia modulates tumor cell escape from the mounted immune response. The tumor cell-immune cell crosstalk in the context of a hypoxic TME tips the balance towards a cold and immunosuppressed microenvironment that is resistant to immune checkpoint inhibitors (ICI). Nonetheless, evidence is emerging that could make hypoxia an asset for improving response to ICI. Tackling the tumor immune contexture has taken on an in silico, digitalized approach with an increasing number of studies applying bioinformatics to deconvolute the cellular and non-cellular elements of the TME. Such approaches have additionally been combined with signature-based proxies of hypoxia to further dissect the turbulent hypoxia-immune relationship. In this review we will be highlighting the mechanisms by which hypoxia impacts immune cell functions and how that could translate to predicting response to immunotherapy in an era of machine learning and computational biology.

Cardiorespiratory anomalies and increased brainstem microglia in a rat model of neonatal opioid withdrawal syndrome.

Infants born with neonatal opioid withdrawal syndrome (NOWS) can display abnormal cardiorespiratory patterns including tachypnea, tachycardia, and impaired ventilatory responses to hypoxia (HVR) and hypercapnia (HCVR). Chronic morphine exposure is associated with increased midbrain microglial expression. Using a rat model of pre- and post-natal morphine exposure, we assessed cardiorespiratory features of NOWS (resting tachycardia and tachypnea) including the attenuated HVR and HCVR and whether they are associated with increased brainstem microglia expression. Pregnant rats (dams) received twice-daily subcutaneous injections of morphine (5 mg/kg) during the third (last) week of pregnancy to simulate 3rd trimester in utero opioid exposure. Offspring then received once-daily subcutaneous injections of morphine (0.5 mg/kg) until postnatal (P) day P10 days of age to simulate postnatal morphine therapy. Cardiorespiratory responses were assessed 24 h later (P11 days) following spontaneous withdrawal. Compared to saline-treated pups, morphine-exposed offspring exhibited tachycardia and tachypnea as well as an attenuated HVR and HCVR. Microglial cell counts were increased in the nucleus tractus solitarius (nTS), dorsal motor nucleus of the vagus (DMNV) and nucleus ambiguous (NAamb), but not the retrapezoid nucleus (RTN) or the non-cardiorespriatory region, the cuneate nucleus (CN). These data suggest that the cardiorespiratory features and autonomic dysregulation in NOWS infants may be associated with altered microglial function in specific brainstem cardiorespiratory control regions.

Hypoxic Processes Induce Complement Activation via Classical Pathway in Porcine Neuroretinas.

Considering the fact that many retinal diseases are yet to be cured, the pathomechanisms of these multifactorial diseases need to be investigated in more detail. Among others, oxidative stress and hypoxia are pathomechanisms that take place in retinal diseases, such as glaucoma, age-related macular degeneration, or diabetic retinopathy. In consideration of these diseases, it is also evidenced that the immune system, including the complement system and its activation, plays an important role. Suitable models to investigate neuroretinal diseases are organ cultures of porcine retina. Based on an established model, the role of the complement system was studied after the induction of oxidative stress or hypoxia. Both stressors led to a loss of retinal ganglion cells (RGCs) accompanied by apoptosis. Hypoxia activated the complement system as noted by higher C3+ and MAC+ cell numbers. In this model, activation of the complement cascade occurred via the classical pathway and the number of C1q+ microglia was increased. In oxidative stressed retinas, the complement system had no consideration, but strong inflammation took place, with elevated TNF, IL6, and IL8 mRNA expression levels. Together, this study shows that hypoxia and oxidative stress induce different mechanisms in the porcine retina inducing either the immune response or an inflammation. Our findings support the thesis that the immune system is involved in the development of retinal diseases. Furthermore, this study is evidence that both approaches seem suitable models to investigate undergoing pathomechanisms of several neuroretinal diseases.

Effects of Intermittent Hypoxia on Cytokine Expression Involved in Insulin Resistance.

Sleep apnea syndrome (SAS) is a prevalent disorder characterized by recurrent apnea or hypoxia episodes leading to intermittent hypoxia (IH) and arousals during sleep. Currently, the relationship between SAS and metabolic diseases is being actively analyzed, and SAS is considered to be an independent risk factor for the development and progression of insulin resistance/type 2 diabetes (T2DM). Accumulating evidence suggests that the short cycles of decreased oxygen saturation and rapid reoxygenation, a typical feature of SAS, contribute to the development of glucose intolerance and insulin resistance. In addition to IH, several pathological conditions may also contribute to insulin resistance, including sympathetic nervous system hyperactivity, oxidative stress, vascular endothelial dysfunction, and the activation of inflammatory cytokines. However, the detailed mechanism by which IH induces insulin resistance in SAS patients has not been fully revealed. We have previously reported that IH stress may exacerbate insulin resistance/T2DM, especially in hepatocytes, adipocytes, and skeletal muscle cells, by causing abnormal cytokine expression/secretion from each cell. Adipose tissues, skeletal muscle, and the liver are the main endocrine organs producing hepatokines, adipokines, and myokines, respectively. In this review, we focus on the effect of IH on hepatokine, adipokine, and myokine expression.

Elevated Monocytic Interleukin-8 Expression under Intermittent Hypoxia Condition and in Obstructive Sleep Apnea Patients.

Obstructive sleep apnea (OSA) is a disease with great cardiovascular risk. Interleukin-8 (IL-8), an important chemokine for monocyte chemotactic migration, was studied under intermittent hypoxia condition and in OSA patients. Monocytic THP-1 cells were used to investigate the effect of intermittent hypoxia on the regulation of IL-8 by an intermittent hypoxic culture system. The secreted protein and mRNA levels were studied by means of enzyme-linked immunosorbent assay and RT/real-time PCR. The chemotactic migration of monocytes toward a conditioned medium containing IL-8 was performed by means of the transwell filter migration assay. Peripheral venous blood was collected from 31 adult OSA patients and RNA was extracted from the monocytes for the analysis of IL-8 expression. The result revealed that intermittent hypoxia enhanced the monocytic THP-1 cells to actively express IL-8 at both the secreted protein and mRNA levels, which subsequently increased the migration ability of monocytes toward IL-8. The ERK, PI3K and PKC pathways were demonstrated to contribute to the activation of IL-8 expression by intermittent hypoxia. In addition, increased monocytic IL-8 expression was found in OSA patients, with disease severity dependence and diurnal changes. This study concluded the monocytic IL-8 gene expression can be activated by intermittent hypoxia and increased in OSA patients.

Tumor-Associated Macrophages and Their Functional Transformation in the Hypoxic Tumor Microenvironment.

Tumor-associated macrophages (TAMs) are some of the most abundant immune cells within tumors and perform a broad repertoire of functions via diverse phenotypes. On the basis of their functional differences in tumor growth, TAMs are usually categorized into two subsets of M1 and M2. It is well established that the tumor microenvironment (TME) is characterized by hypoxia along with tumor progression. TAMs adopt an M1-like pro-inflammatory phenotype at the early phases of oncogenesis and mediate immune response that inhibits tumor growth. As tumors progress, anabatic hypoxia of the TME gradually induces the M2-like functional transformation of TAMs by means of direct effects, metabolic influence, lactic acidosis, angiogenesis, remodeled stroma, and then urges them to participate in immunosuppression, angiogenesis and other tumor-supporting procedure. Therefore, thorough comprehension of internal mechanism of this TAM functional transformation in the hypoxic TME is of the essence, and might provide some novel insights in hypoxic tumor immunotherapeutic strategies.

Trophoblast-derived interleukin 9 mediates immune cell conversion and contributes to maternal-fetal tolerance.

In the maternal-fetal crosstalk, fetal derived trophoblast cells can secret several molecules to regulate immune tolerance such as cytokines and chemokines, besides human leukocyte antigens (HLA) providing. However, the mechanism of these factors in pregnancy is still unknown. Our previous study showed that IL9 could be secreted by trophoblasts and exerted a positive effect on trophoblasts themselves through autocrine signaling. Given the immunoregulatory function of IL9 and its expression in trophoblasts, we hypothesize that IL9 contributes to maternal-fetal tolerance by regulating immune cells, especially CD14+ dendritic cells (DCs) and naïve CD4 + T cells who have essential roles in maternal-fetal immune tolerance. We performed a series of experiments, finding that HTR8/SVneo cells could secrete IL9 in vitro, and this secretion was decreased under hypoxia; both CD14 + DCs and naïve CD4 + T cells expressed IL9 receptors, indicating potential interactions among these cells. In CD14 + DCs, trophoblast-derived IL9 promoted the immature differentiation, and induced the secretion of Th2 cytokines, including IL4 and IL10, shifting the Th1/Th2 ratio to Th2. In naïve CD4 + T cells, IL9 also increased Foxp3 expression and promoted the secretion of Treg cytokines, including TGFß and IL10, inhibiting pro-inflammatory Th17. Therefore, trophoblasts may act as fetal-derived immune cells to maintain maternal-fetal tolerance by secreting IL9. Given that trophoblast derived IL9 is decreased in preeclampsia, our study provides a new insight into maternal-fetal immunology and immunological disorders in abnormal pregnancy.

Effects of hypoxia and hyperoxia on growth parameters and transcription levels of growth, immune system and stress related genes in rainbow trout.

Hypoxia and hyperoxia are disparate stressors which can have destructive influences on fish growth and physiology. It is yet to be determined if hypoxia and hyperoxia have a cumulative effect in aquatic ecosystems that affect biological parameters in fish, and to understand if this is associated with gene expression. Here we address whether growth performance and expressions of growth, immune system and stress related genes were affected by hypoxia and hyperoxia in fish. Rainbow trout was chosen as the study organism due to its excellent service as biomonitor. After an acclimatization period, fish were exposed to hypoxia (4.0 ± 0.5 ppm O2), normoxia (7.5 ± 0.5 ppm O2) and hyperoxia (12 ± 1.2 ppm O2) for 28 days. At 6 h, 12 h, 24 h, 48 h, 72 h and 28 days, samples were collected. Hypoxia and hyperoxia negatively affected weight gain (WG), specific growth rate (SGR), survival rate (SR) and feed conversion ratio (FCR). The best WG, SGR, SR and FCR values occurred in fish exposed to normoxia, whereas hypoxia was most suppressive on growth and hyperoxia showed intermediate suppression of these parameters. Gene expression analyses were performed in liver and results revealed that long term exposure caused reduced growth hormone-I (GH-I) and insulin like growth factor I-II (IGF I-II) levels in both hypoxia and hyperoxia-treated fish. Heat shock protein (HSP70) levels increased in both hypoxia and hyperoxia treatment, and both exposures caused elevation of leptin (LEP) expression in long-term exposure. Overall data indicate that both hypoxia and hyperoxia cause stress in rainbow trout and negatively affects growth parameters.

A combined hypoxia and immune gene signature for predicting survival and risk stratification in triple-negative breast cancer.

BACKGROUND: Increasing evidence showed that the clinical significance of the interaction between hypoxia and immune status in tumor microenvironment. However, reliable biomarkers based on the hypoxia and immune status in triple-negative breast cancer (TNBC) have not been well established. This study aimed to explore a gene signature based on the hypoxia and immune status for predicting prognosis, risk stratification, and individual treatment in TNBC. METHODS: Hypoxia-related genes (HRGs) and Immune-related genes (IRGs) were identified using the weighted gene co-expression network analysis (WGCNA) method and the single-sample gene set enrichment analysis (ssGSEA Z-score) with the transcriptomic profiles from Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort. Then, prognostic hypoxia and immune based genes were identified in TNBC patients from the METABRIC (N = 221), The Cancer Genome Atlas (TCGA) (N = 142), and GSE58812 (N = 107) using univariate cox regression model. A robust hypoxia-immune based gene signature for prognosis was constructed using the least absolute shrinkage and selection operator (LASSO) method. Based on the cross-cohort prognostic hypoxia-immune related gene signature, a comprehensive index of hypoxia and immune was developed and two risk groups with distinct hypoxia-immune status were identified. The prognosis value, hypoxia and immune status, and therapeutic response in different risk groups were analyzed. Furthermore, a nomogram was constructed to predict the prognosis for individual patients, and an independent cohort from the gene expression omnibus (GEO) database was used for external validation. RESULTS: Six cross-cohort prognostic hypoxia-immune related genes were identified to establish the comprehensive index of hypoxia and immune. Then, patients were clustered into high- and low-risk groups based on the hypoxia-immune status. Patients in the high-risk group showed poorer prognoses to their low-risk counterparts, and the nomogram we constructed yielded favorable performance to predict survival and risk stratification. Besides, the high-risk group had a higher expression of hypoxia-related genes and correlated with hypoxia status in tumor microenvironment. The high-risk group had lower fractions of activated immune cells, and exhibited lower expression of immune checkpoint markers. Furthermore, the ratio of complete response (CR) was greatly declined, and the ratio of breast cancer related events were significantly elevated in the high-risk group. CONCLUSION: The hypoxia-immune based gene signature we constructed for predicting prognosis was developed and validated, which may contribute to the optimization of risk stratification for prognosis and personalized treatment in TNBC patients.

Macrophage Polarization States in the Tumor Microenvironment.

The M1/M2 macrophage paradigm plays a key role in tumor progression. M1 macrophages are historically regarded as anti-tumor, while M2-polarized macrophages, commonly deemed tumor-associated macrophages (TAMs), are contributors to many pro-tumorigenic outcomes in cancer through angiogenic and lymphangiogenic regulation, immune suppression, hypoxia induction, tumor cell proliferation, and metastasis. The tumor microenvironment (TME) can influence macrophage recruitment and polarization, giving way to these pro-tumorigenic outcomes. Investigating TME-induced macrophage polarization is critical for further understanding of TAM-related pro-tumor outcomes and potential development of new therapeutic approaches. This review explores the current understanding of TME-induced macrophage polarization and the role of M2-polarized macrophages in promoting tumor progression.

A hypoxia risk signature for the tumor immune microenvironment evaluation and prognosis prediction in acute myeloid leukemia.

Acute myeloid leukemia (AML) is the most prevalent form of acute leukemia. Patients with AML often have poor clinical prognoses. Hypoxia can activate a series of immunosuppressive processes in tumors, resulting in diseases and poor clinical prognoses. However, how to evaluate the severity of hypoxia in tumor immune microenvironment remains unknown. In this study, we downloaded the profiles of RNA sequence and clinicopathological data of pediatric AML patients from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database, as well as those of AML patients from Gene Expression Omnibus (GEO). In order to explore the immune microenvironment in AML, we established a risk signature to predict clinical prognosis. Our data showed that patients with high hypoxia risk score had shorter overall survival, indicating that higher hypoxia risk scores was significantly linked to immunosuppressive microenvironment in AML. Further analysis showed that the hypoxia could be used to serve as an independent prognostic indicator for AML patients. Moreover, we found gene sets enriched in high-risk AML group participated in the carcinogenesis. In summary, the established hypoxia-related risk model could act as an independent predictor for the clinical prognosis of AML, and also reflect the response intensity of the immune microenvironment in AML.

An Eight-Gene Hypoxia Signature Predicts Survival in Pancreatic Cancer and Is Associated With an Immunosuppressed Tumor Microenvironment.

Intratumoral hypoxia is a widely established element of the pancreatic tumor microenvironment (TME) promoting immune escape, tumor invasion, and progression, while contributing to treatment resistance and poor survival. Despite this critical role, hypoxia is underrepresented in molecular signatures of pancreatic ductal adenocarcinoma (PDA) and concurrent investigations into the hypoxia-immune status are lacking. In this work a literature-based approach was applied to derive an eight-gene hypoxia signature that was validated in fourteen cancer cell lines and in a cohort of PDA. The eight-gene hypoxia signature was significantly associated with overall survival in two distinct PDA datasets and showed independent prognostic value in multivariate analysis. Comparative analysis of tumors according to their hypoxia score (high versus low) determined that tumors with high hypoxia were significantly less enriched in cytotoxic T-cells, and cytolytic activity. In addition, they had lower expression of cytokines and tumor inflammatory markers, pointing to the signature's ability to discern an immune "cold", hypoxic TME. Combining the signature with an immune metric highlighted a worse survival probability in patients with high hypoxia and low immune reactivity, indicating that this approach could further refine survival estimates. Hypoxia as determined by our signature, was significantly associated with certain immune checkpoint inhibitors (ICI) biomarkers, suggesting that the signature reflects an aspect of the TME that is worth pursuing in future clinical trials. This is the first work of its kind in PDA, and our findings on the hypoxia-immune tumor contexture are not only relevant for ICI but could also guide combinatorial hypoxia-mediated therapeutic strategies in this cancer type.