bims-mampoc Biomed News
on Macrophage metabolism and polarization in cancer
Issue of 2022–03–06
eleven papers selected by
Alessandra Castegna, University of Bari “Aldo Moro”



  1. Cell Death Dis. 2022 Mar 04. 13(3): 206
      Aerobic glycolysis (the Warburg effect) has been demonstrated to facilitate tumor progression by producing lactate, which has important roles as a proinflammatory and immunosuppressive mediator. However, how aerobic glycolysis is directly regulated is largely unknown. Here, we show that ectopic Zeb1 directly increases the transcriptional expression of HK2, PFKP, and PKM2, which are glycolytic rate-determining enzymes, thus promoting the Warburg effect and breast cancer proliferation, migration, and chemoresistance in vitro and in vivo. In addition, Zeb1 exerts its biological effects to induce glycolytic activity in response to hypoxia via the PI3K/Akt/HIF-1α signaling axis, which contributes to fostering an immunosuppressive tumor microenvironment (TME). Mechanistically, breast cancer cells with ectopic Zeb1 expression produce lactate in the acidic tumor milieu to induce the alternatively activated (M2) macrophage phenotype through stimulation of the PKA/CREB signaling pathway. Clinically, the expression of Zeb1 is positively correlated with dysregulation of aerobic glycolysis, accumulation of M2-like tumor-associated macrophages (TAMs) and a poor prognosis in breast cancer patients. In conclusion, these findings identify a Zeb1-dependent mechanism as a driver of breast cancer progression that acts by stimulating tumor-macrophage interplay, which could be a viable therapeutic target for the treatment of advanced human cancers.
    DOI:  https://doi.org/10.1038/s41419-022-04632-z
  2. Front Oncol. 2022 ;12 772615
      Triple negative breast cancer (TNBC) refers to the subtype of breast cancer which is negative for ER, PR, and HER-2 receptors. Tumor-associated macrophages (TAMs) refer to the leukocyte infiltrating tumor, derived from circulating blood mononuclear cells and differentiating into macrophages after exuding tissues. TAMs are divided into typical activated M1 subtype and alternately activated M2 subtype, which have different expressions of receptors, cytokines and chemokines. M1 is characterized by expressing a large amount of inducible nitric oxide synthase and TNF-α, and exert anti-tumor activity by promoting pro-inflammatory and immune responses. M2 usually expresses Arginase 1 and high levels of cytokines, growth factors and proteases to support their carcinogenic function. Recent studies demonstrate that TAMs participate in the process of TNBC from occurrence to metastasis, and might serve as potential biomarkers for prognosis prediction.
    Keywords:  ER; HER-2; PR; TAMs; TNBC
    DOI:  https://doi.org/10.3389/fonc.2022.772615
  3. Front Immunol. 2022 ;13 740588
      Infiltrating T-regulatory cells in the tumor microenvironment is a key impediment to immunotherapy and is linked to a poor prognosis. We found that tumor-infiltrating Tregs express a higher expression of the chemokine receptor CCR4 than peripheral Tregs in breast cancer patients. CCL22 and CCL17 are released by tumor cells and tumor-associated macrophages, attracting CCR4+ Tregs to the tumor site. The Treg lineage-specific transcription factor FOXP3 changes the CCR4 promoter epigenetically in conjunction with HAT1 to provide a space for FOXP3 binding and activation of the CCR4 gene. To increase CCR4 expression in Tregs, the FOXP3/HAT1 axis is required for permissive (K23 and K27) or repressive (K14 and K18) acetylation of histone-3. In murine breast and melanoma tumor models, genetic ablation of FOXP3 reduced CCR4+ Treg infiltration and tumor size while also restoring anti-tumor immunity. Overexpression of FOXP3, on the other hand, increased CCR4+ Treg infiltration, resulting in a decreased anti-tumor immune response and tumor progression. These findings point to FOXP3 playing a new role in the tumor microenvironment as a transcriptional activator of CCR4 and a regulator of Treg infiltration.
    Keywords:  CCR4; FOXP3; Treg cells; Treg infiltration; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/fimmu.2022.740588
  4. Yakugaku Zasshi. 2022 ;142(3): 229-239
      My research area in the pharmaceutical industry is innate immunity, especially in phagocytic cells. First, I studied the heat-stable growth factor of peripheral macrophages in tumorous ascitic fluid and found that lipoproteins are an influencing factor. Later, my colleagues and I found that lipid-containing substances, namely, oxidized low-density lipoprotein, dead neutrophils, or purified lipids that could be scavenged by macrophages, induce their growth. From the series of this study, I concluded that phagocytic substances induce macrophage growth by autocrine stimulation of granulocyte-macrophage colony-stimulating factor (GM-CSF). During the study, we found that neutrophils have growth-inhibitory effects against a variety of cells. Then, I elucidated that the primary factor is a zinc-binding protein, calprotectin, an abundant protein complex in the neutrophil cytosol. I found that calprotectin induces apoptosis in many cell types, including tumor cells and normal fibroblasts, and that the zinc-binding capacity is essential for its activity. Microscopic observations revealed that neutrophil extract contains factor-inducing three-dimensional cell aggregation of human mammary carcinoma, MCF-7. I elucidated that cathepsin G is responsible for this activity and that its effect is dependent on the activation of insulin-like growth factor-1. I believe that this modest, albeit novel, observation was crucial to my thirty-nine-year-long career researching phagocytic cells.
    Keywords:  calprotectin; cathepsin G; macrophage growth; neutrophil
    DOI:  https://doi.org/10.1248/yakushi.21-00191
  5. Ann N Y Acad Sci. 2022 Mar 05.
      A major cause of gynecological cancer -related deaths worldwide, ovarian cancer is characterized by heterogeneity in both tumor cells and the tumor microenvironment (TME). Our study aimed to characterize tumor cell heterogeneity and the infiltration of M2 tumor-associated macrophages (TAMs) in the ovarian cancer TME by single-cell RNA-Seq (scRNA-Seq) analysis combined with bulk RNA sequencing (bulk RNA-Seq). Several highly variable genes were identified in ovarian cancer tissues, and tumor cell heterogeneity and infiltrating immune tumor cell heterogeneity were characterized in ovarian cancer cells. M2 TAMs in the TME were the predominant phenotype of TAM. Further, M2 TAM infiltration in the TME was negatively correlated with poor prognosis of ovarian cancer patients. Four M2 TAM-associated genes (SLAMF7, GNAS, TBX2-AS1, and LYPD6) correlated with the prognostic survival of ovarian cancer patients. Knockdown of SLAMF7 or GNAS mRNA repressed malignancy and cisplatin resistance of ovarian cancer cells. ScRNA-Seq combined with bulk RNA-Seq identified the same four genes associated with M2 TAMs. The prognostic risk score model based on these four genes may hold favorable predictive value for the prognosis of ovarian cancer patients.
    Keywords:  M2 tumor-associated macrophage; bulk RNA sequencing; epithelial-mesenchymal transition; ovarian cancer; single-cell RNA sequencing; tumor cell heterogeneity; tumor microenvironment
    DOI:  https://doi.org/10.1111/nyas.14748
  6. Curr Oncol Rep. 2022 Mar 01.
       PURPOSE OF REVIEW: In this review, we update the latest findings on the impacts of FA metabolism reprogramming on the phenotypes and functions of immune cells in tumor-related immune responses. We also summarize the combinatorial interventions of FA metabolism, which improve the effects of current immunotherapies.
    RECENT FINDINGS: Multiple studies have shown that either the abnormality in signaling pathways or nutrition competition in the TME can lead to phenotypic reprogramming of FA metabolism and functional changes in tumor-infiltrating immune cells, thereby influencing the therapeutic effects of cancer immunotherapies. Accordingly, regulating FA metabolism in immune cells has emerged and become promising approaches to synergize with immunotherapies. One of the mechanisms behind suboptimal therapeutic effects of immunotherapies is metabolic reprogramming of the TME that impairs immunosuppressive activity. FA metabolism is a crucial process involved in the survival and function of primary immune cells. It is of great significance to explore the feasibility of overcoming FA metabolic barriers to improve cancer immunotherapy.
    Keywords:  Cancer immunotherapy; Fatty acid; Immune cells; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s11912-022-01223-1
  7. J Bone Miner Res. 2022 Feb 27.
      Enchondromas and chondrosarcomas are common cartilage neoplasms that are either benign or malignant respectively. The majority of these tumors harbor mutations in either IDH1 or IDH2. Glutamine metabolism has been implicated as a critical regulator of tumors with IDH mutations. Using genetic and pharmacological approaches, we demonstrated that glutaminase-mediated glutamine metabolism played distinct roles in enchondromas and chondrosarcomas with IDH1 or IDH2 mutations. Glutamine affected cell differentiation and viability in these tumors differently through different downstream metabolites. During murine enchondroma-like lesion development, glutamine-derived α-ketoglutarate promoted hypertrophic chondrocyte differentiation and regulated chondrocyte proliferation. Deletion of glutaminase in chondrocytes with Idh1 mutation increased the number and size of enchondroma-like lesions. In contrast, pharmacological inhibition of glutaminase in chondrosarcoma xenografts reduced overall tumor burden partially because glutamine-derived non-essential amino acids played an important role in preventing cell apoptosis. This study demonstrates that glutamine metabolism plays different roles in tumor initiation and cancer maintenance. Supplementation of α-ketoglutarate and inhibiting GLS may provide a therapeutic approach to suppress enchondroma and chondrosarcoma tumor growth respectively.
    Keywords:  CARTILAGE TUMORS; CHONDROCYTE DIFFERENTIATION; GLUTAMINE METABOLISM; GROWTH PLATE; ISOCITRATE DEHYDROGENASE
    DOI:  https://doi.org/10.1002/jbmr.4532
  8. Free Radic Biol Med. 2022 Feb 24. pii: S0891-5849(22)00077-6. [Epub ahead of print]182 79-92
      Ovarian cancer has the most mortality of all gynecologic malignancies. High-grade serous ovarian carcinoma (HGSOC) is the most common and deadly type of ovarian cancer. Tumor recurrence occurs due to the emergence of chemotherapy resistance. Thus, searching for new therapeutic strategies is essential for the management of ovarian cancer. Deregulation of iron metabolism can be used by ovarian cancer cells to survive, proliferate and metastasize. Here we report that sodium molybdate, a soluble molybdenum (Mo) compound, induces the elevation of the labile iron pool (LIP) in ovarian cancer cells, correlated with the down-regulation of genes involved in extracellular matrix organization. Sodium molybdate also induces depletion of glutathione (GSH) through mediating the production of nitric oxide (NO). Elevation of LIP and depletion of GSH promote the ferroptosis of ovarian cancer cells. Meanwhile, nitric oxide induces mitochondrial damage through inhibiting mitochondrial aconitase activity, ATP production, and mitochondrial membrane potential, leading to apoptosis of ovarian cancer cells. In vivo study shows that sodium molybdate reduces tumor burden in nude mice. Xenografts treated with sodium molybdate are characterized by obvious iron accumulation, increased expression of the iron storage protein ferritin, and lipid peroxide product 4-hydroxynonenal. In addition, an elevated percentage of apoptotic cells is observed in xenografts treated with sodium molybdate. Taken together, these results demonstrate that sodium molybdate can induce both ferroptosis and apoptosis of ovarian cancer cells, making it a potential therapeutic candidate for ovarian cancer.
    Keywords:  Apoptosis; Chemoresistance; Ferroptosis; Ovarian cancer; Sodium molybdate
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.02.023
  9. Front Immunol. 2022 ;13 832418
      During tumor development, invasion and metastasis, the intimate interaction between tumor and stroma shapes the tumor microenvironment and dictates the fate of tumor cells. Stromal cells can also influence anti-tumor immunity and response to immunotherapy. Understanding the molecular mechanisms that govern this complex and dynamic interplay, thus is important for cancer diagnosis and therapy. Proteolytic enzymes that are expressed and secreted by both cancer and stromal cells play important roles in modulating tumor-stromal interaction. Among, several serine proteases such as fibroblast activation protein, urokinase-type plasminogen activator, kallikrein-related peptidases, and granzymes have attracted great attention owing to their elevated expression and dysregulated activity in the tumor microenvironment. This review highlights the role of serine proteases that are mainly derived from stromal cells in tumor progression and associated theranostic applications.
    Keywords:  extracellular matrix remodeling; fibroblast activation protein; granzyme; kallikrein; serine protease; signaling pathways ; tumor-stromal interaction; urokinase plasminogen activator
    DOI:  https://doi.org/10.3389/fimmu.2022.832418
  10. J Tissue Eng Regen Med. 2022 Feb 28.
      Macrophages have two functionalized phenotypes, M1 and M2, and the regulation of M1/M2 polarization of macrophages is critical for tissue repair. Tissue-derived immune factors are considered the major drivers of macrophage polarization. Based on the main cytokine-induced polarization pathways, we tested the effect of electrical stimulation (ES) of macrophages on the regulation of M1/M2 polarization and a possible synergistic effect with the cytokines. Indium tin oxide (ITO) planar microelectrodes were used to produce ES under different voltages, frequencies and waveforms. We evaluated the influence of ES on the cytokine-induced M1/M2 polarization using mouse bone marrow-derived macrophages cultured with both lipopolysaccharide (LPS)/IFN-γ factors and IL-4 factors for M1 and M2, respectively. The results showed that ES promoted the cytokine-induced macrophage polarization. Importantly, we found that stimulation with a square waveform selectively promoted LPS/IFN-γ-induced M1 polarization, while stimulation with a sinusoidal waveform promoted both LPS/IFN-γ-induced M1, and IL-4-induced M2 polarization. Mechanistically, stimulation with a square waveform affected the intracellular ion concentration, whereas stimulation with a sinusoidal waveform promoted both the intracellular ion concentration and membrane receptors. We hereby establish an ES-mediated strategy for immunomodulation via macrophage polarization.
    Keywords:  cytokine-induced M1/M2 polarization; electrical stimulation; macrophage; waveform
    DOI:  https://doi.org/10.1002/term.3292
  11. J Clin Invest. 2022 Mar 03. pii: e150846. [Epub ahead of print]
      Anti-CTLA-4 + anti-PD-1/PD-L1 combination is the most effective cancer immunotherapy but causes high incidence of immune-related adverse events (irAE). Here we report that targeting of HIF-1α suppressed PD-L1 expression on tumor cells and tumor-infiltrated myeloid cells, but unexpectedly induced PD-L1 in normal tissues by an IFNγ-dependent mechanism. Targeting the HIF-1α-PD-L1 axis in tumor cells reactivated tumor-infiltrating lymphocytes (TILs) and caused tumor rejection. The HIF-1α inhibitor echinomycin potentiated cancer immunotherapeutic effects of anti-CTLA-4 therapy with efficacy comparable to anti-CTLA-4+anti-PD-1 antibodies. However, while anti-PD-1 exacerbated irAE triggered by Ipilimumab, echinomycin protected mice against irAE by increasing PD-L1 levels in normal tissues. Our data suggest that targeting HIF-1α fortifies the immune tolerance function of the PD-1:PD-L1 checkpoint in normal tissues but abrogates its immune evasion function in the tumor microenvironment (TME) to achieve safer and more effective immunotherapy.
    Keywords:  Cancer immunotherapy; Therapeutics
    DOI:  https://doi.org/10.1172/JCI150846