bims-stacyt 2021-09-05 papers

Cytokine Growth Factor Rev. 2021 Aug 28. pii: S1359-6101(21)00064-2. [Epub ahead of print]

Small extracellular vesicle-mediated bidirectional crosstalk between neutrophils and tumor cells.

Dominique S Rubenich, Natália Omizzollo, Mirosław J Szczepański, Torsten E Reichert, Theresa L Whiteside, Nils Ludwig, Elizandra Braganhol.

Neutrophils are the first line of defense against tissue injury and play an important role in tumor progression. Tumor-associated neutrophils (TANs) mediate pro-tumor immunosuppressive activity and their infiltration into tumors is associated with poor outcome in a variety of malignant diseases. The tumor cell-neutrophil crosstalk is mediated by small extracellular vesicles (sEVs) also referred to as exosomes which represent a major mechanism for intercellular communication. This review will address the role of neutrophil-derived sEVs (NEX) in reprogramming the TME and on mechanisms that regulate the dual potential of NEX to promote tumor progression on one hand and suppress tumor growth on the other. Emerging data suggest that both, NEX and tumor-derived sEVs (TEX) carry complex molecular cargos which upon delivery to recipient cells in the tumor microenvironment (TME) modulate their behavior and reprogram them to mediate pro-inflammatory or immunosuppressive responses. Although it remains unknown how the balance between the often conflicting signaling of TEX and NEX is regulated, this review is an attempt to provide insights into mechanisms that underpin this complex bidirectional crosstalk. A better understanding of the signals NEX process or deliver in the TME might lead to the development of novel approaches to the control of tumor progression in the future.

Keywords: Neutrophils; Small extracellular vesicles; Tumor microenvironment (TME); Tumor-associated neutrophils (TAN); Tumor-derived exosomes (TEX)

DOI: https://doi.org/10.1016/j.cytogfr.2021.08.002

BMC Cancer. 2021 Sep 03. 21(1): 990

Head and neck squamous cell carcinoma cell lines have an immunomodulatory effect on macrophages independent of hypoxia and toll-like receptor 9.

Tamiko Ishizu, Dominik Eichin, Artur Padzik, Sanni Tuominen, Reidar Grénman, Marko Salmi, Tove J Grönroos, Johanna M Tuomela.

BACKGROUND: A low tissue oxygen level, < 1% O2, is a typical characteristic inside of solid tumors in head and neck cancer (HNSCC) affecting a wide array of cell populations, such as macrophages. However, the mechanisms of how hypoxia influences macrophages are not yet fully elucidated. Our research aimed to study the effect of soluble mediators produced by hypoxic cancer cells on macrophage polarization. Furthermore, we studied the effect of a hypoxic microenvironment on the expression of tumorigenic toll-like receptor 9 (TLR9) and the consecutive macrophage polarization.
METHODS: Conditioned media (CMNOX or CMHOX) from cell lines UT-SCC-8, UT-SCC-74A, FaDu, MDA-MB-231 and HaCat cultured under normoxic (21% O2) and hypoxic (1% O2) conditions were used to polarize human monocyte-derived macrophages. Macrophage polarization was measured by flow cytometry and the production of cytokine mRNA using Taqman qPCR. To study the role of TLR9 in macrophage polarization, the lentiviral CRISPR/Cas9 method was used to establish a stable FaDuTLR9def clone.
RESULTS: Our results demonstrate that the soluble mediators produced by the cancer cells under normoxia polarize macrophages towards a hybridized M1/M2a/M2c phenotype. Furthermore, the results suggest that hypoxia has a limited role in altering the array of cancer-produced soluble factors affecting macrophage polarization and cytokine production. Our data also indicates that increased expression of TLR9 due to hypoxia in malignant cells does not markedly influence the polarization of macrophages. TLR9 transcriptional response to hypoxia is dissimilar to a HIF1-α-regulated LDH-A. This may indicate a context-dependent expression of TLR9 under hypoxia.
CONCLUSIONS: HNSCC cell lines affect both macrophage activity (polarization) and functionality (cytokines), but with exception to iNOS expression, the effects appear independent of hypoxia and TLR9.

Keywords: Anti-cancer immunomodulation; Head and neck squamous cell carcinoma; Hypoxia; Immune evasion; Immunoediting; Innate immune response; Macrophage polarization; TLR9

DOI: https://doi.org/10.1186/s12885-021-08357-8

Cell Mol Biol Lett. 2021 Sep 03. 26(1): 40

HIF-1α/JMJD1A signaling regulates inflammation and oxidative stress following hyperglycemia and hypoxia-induced vascular cell injury.

Min Zhao, Shaoting Wang, Anna Zuo, Jiaxing Zhang, Weiheng Wen, Weiqiang Jiang, Hong Chen, Donghui Liang, Jia Sun, Ming Wang.

BACKGROUND: Endothelial cell (EC) injury accelerates the progression of diabetic macrovascular complications. Hypoxia is an important cause of EC injury. Hypoxia-inducible factor-1 alpha (HIF-1α) is an important hypoxia regulatory protein. Our previous studies showed that high-glucose and hypoxic conditions could upregulate HIF-1α expression and enhance EC inflammatory injury, independently of the nuclear factor kappa-B (NF-κB) pathway. However, it is not clear whether HIF-1α plays a role in vascular disease through epigenetic-related mechanisms.
METHODS: We conducted gene expression analysis and molecular mechanistic studies in human umbilical vein endothelial cells (HUVECs) induced by hyperglycemia and hypoxia using RNA sequencing (RNA-seq) and small interfering HIF-1α (si-HIF-1α). We determined HIF-1α and Jumonji domain-containing protein 1 A (JMJD1A) expression by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot, analyzed inflammatory protein secretion in the cell supernatant by enzymelinked immunosorbent assay (ELISA), and assessed protein interaction between HIF-1α and JMJD1A by chromatin immunoprecipitation (Ch-IP). We used the Cell Counting Kit8 (CCK-8) assay to analyze cell viability, and assessed oxidative stress indicators by using a detection kit and flow cytometry.
RESULTS: High glucose and hypoxia up-regulated HIF-1α expression, and down-regulated HIF-1α decreased the level of inflammation and oxidative stress in HUVECs. To determine the downstream pathways, we observed histone demethylases genes and related pathway by RNA-sEq. Among these, JMJD1A was the most upregulated gene in histone demethylases. Moreover, we observed that HIF-1α bound to the promoter of JMJD1A, and the ameliorative effects of si-HIF-1α on oxidative stress and inflammatory cytokines in high-glucose and hypoxia-induced HUVECs were reversed by JMJD1A overexpression. Furthermore, knockdown of JMJD1A decreased inflammatory and oxidative stress injury. To determine the JMJD1A-related factors, we conducted gene expression analysis on JMJD1A-knockdown HUVECs. We observed that downregulation of inflammation and the oxidative stress pathway were enriched and FOS and FOSB might be important protective transcription factors.
CONCLUSIONS: These findings provide novel evidence that the HIF-1α/JMJD1A signaling pathway is involved in inflammation and oxidative stress in HUVECs induced by high glucose and hypoxia. Also, this pathway might act as a novel regulator of oxidative stress and inflammatory-related events in response to diabetic vascular injury and thus contribute to the pathological progression of diabetes and vascular disease.

Keywords: Diabetes; Epigenetics; Hypoxia-inducible factor-1 alpha; Vascular disease

DOI: https://doi.org/10.1186/s11658-021-00283-8

Chemosphere. 2021 Nov;pii: S0045-6535(21)01621-0. [Epub ahead of print]282 131149

Formaldehyde reinforces pro-inflammatory responses of macrophages through induction of glycolysis.

Huijuan Ma, Jinxuan Lin, Linyi Li, Zhaoqian Ding, Ping Huang, Xiaodong Song, Kaiyan Lou, Wei Wang, Huan Xu.

Formaldehyde (FA) is widely used in chemical industry, which is also known as a common indoor air pollutant. Exposure of FA has been associated with multiple detrimental health effects. Our previous study showed that FA could inhibit the development of T lymphocytes in mice, leading to impaired immune functions. Macrophages are important innate immune cells which trigger inflammatory responses in tissues. In the present study, FA exposure at 2.0 mg/m3 was found to enhance the pro-inflammatory responses of macrophages in male BALB/c mice, which was confirmed by elevated pro-inflammatory cytokine release and NO secretion in macrophages isolated from the FA-exposed mice and in vitro macrophage models upon lipopolysaccharide stimulation. Glycolysis is the key metabolic process for the classical activation of macrophages, which was found to be elevated in the in vitro macrophage models treated with FA at 50 and 100 μM concentrations for 18 h. HIF-1α and the associated proteins in its signaling cascade, which are known to mediate glycolytic metabolism and inflammatory responses, were found to be upregulated by 50 and 100 μM FA in THP-1 derived and RAW264.7 macrophage models, and the enhanced pro-inflammatory responses induced by 100 μM FA were reversed by inhibitory compounds interfering with glucose metabolism or suppressing HIF-1α activity. Collectively, the results in this study revealed that FA could enhance the pro-inflammatory responses of macrophages through the induction of glycolysis, which outlined the FA-triggered metabolic and functional alterations in immune cells.

Keywords: Formaldehyde; Glycolysis; HIF-1α; Lipopolysaccharide stimulation; Macrophage; Pro-inflammatory responses

DOI: https://doi.org/10.1016/j.chemosphere.2021.131149

Semin Immunol. 2021 Aug 27. pii: S1044-5323(21)00016-6. [Epub ahead of print] 101485

Metabolic regulation of T cells in the tumor microenvironment by nutrient availability and diet.

Steven Zhao, Ronal M Peralta, Natalia Avina-Ochoa, Greg M Delgoffe, Susan M Kaech.

Recent advances in immunotherapies such as immune checkpoint blockade (ICB) and chimeric antigen receptor T cells (CAR-T) for the treatment of cancer have generated excitement over their ability to yield durable, and potentially curative, responses in a multitude of cancers. These findings have established that the immune system is capable of eliminating tumors and led us to a better, albeit still incomplete, understanding of the mechanisms by which tumors interact with and evade destruction by the immune system. Given the central role of T cells in immunotherapy, elucidating the cell intrinsic and extrinsic factors that govern T cell function in tumors will facilitate the development of immunotherapies that establish durable responses in a greater number of patients. One such factor is metabolism, a set of fundamental cellular processes that not only sustains cell survival and proliferation, but also serves as a means for cells to interpret their local environment. Nutrient sensing is critical for T cells that must infiltrate into a metabolically challenging tumor microenvironment and expand under these harsh conditions to eliminate cancerous cells. Here we introduce T cell exhaustion with respect to cellular metabolism, followed by a discussion of nutrient availability at the tumor and organismal level in relation to T cell metabolism and function to provide rationale for the study and targeting of metabolism in anti-tumor immune responses.

Keywords: Cancer metabolism; Immuno-oncology; Immunometabolism; Immunotherapy; T cells; Tumor microenvironment

DOI: https://doi.org/10.1016/j.smim.2021.101485