M2-polarized macrophages contribute to neovasculogenesis, leading to relapse of oral cancer following radiation

Okubo, Masaki; Kioi, Mitomu; Nakashima, Hideyuki; Sugiura, Kei; Mitsudo, Kenji; Aoki, Ichiro; Taniguchi, Hideki; Tohnai, Iwai

doi:10.1038/srep27548

Cited by 81 publications

(56 citation statements)

References 46 publications

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“…The polarization of TAMs toward M1 phenotype upon inhibition of EphB4-ephrin-B2 is most evident when combined with RT. In oral cavity cancers, the recolonization of tumors by M2-like macrophages post-RT has also been shown to elicit the secretion of pro-angiogenic factors that contribute to neo-angiogenesis, favoring tumor regrowth (61). In our HNSCC model, we show that the combined treatment with an EphB4-ephrin-B2 inhibitor and RT decreases macrophages with the M2 phenotype.…”

Section: Discussionmentioning

confidence: 57%

Inhibition of EphB4–Ephrin-B2 Signaling Reprograms the Tumor Immune Microenvironment in Head and Neck Cancers

et al. 2019

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Identifying targets present in the tumor microenvironment that contribute to immune evasion has become an important area of research. In this study, we identified EphB4-ephrin-B2 signaling as a regulator of both innate and adaptive components of the immune system. EphB4 belongs to receptor tyrosine kinase family that interacts with ephrin-B2 ligand at sites of cell-cell contact, resulting in bidirectional signaling. We found that EphB4-ephrin-B2 inhibition alone or in combination with radiation (RT) reduced intratumoral regulatory T cells (Tregs) and increased activation of both CD8 þ and CD4 þ Foxp3 À T cells compared with the control group in an orthotopic head and neck squamous cell carcinoma (HNSCC) model. We also compared the effect of EphB4-ephrin-B2 inhibition combined with RT with combined anti-PDL1 and RT and observed similar tumor growth suppression, particularly at early time-points. A patient-derived xenograft model showed reduction of tumor-associated M2 macrophages and favored polarization towards an antitumoral M1 phenotype following EphB4-ephrin-B2 inhibition with RT. In vitro, EphB4 signaling inhibition decreased Ki67-expressing Tregs and Treg activation compared with the control group. Overall, our study is the first to implicate the role of EphB4-ephrin-B2 in tumor immune response. Moreover, our findings suggest that EphB4-ephrin-B2 inhibition combined with RT represents a potential alternative for patients with HNSCC and could be particularly beneficial for patients who are ineligible to receive or cannot tolerate anti-PDL1 therapy.Significance: These findings present EphB4-ephrin-B2 inhibition as an alternative to anti-PDL1 therapeutics that can be used in combination with radiation to induce an effective antitumor immune response in patients with HNSCC.

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Section: Discussionmentioning

confidence: 57%

Inhibition of EphB4–Ephrin-B2 Signaling Reprograms the Tumor Immune Microenvironment in Head and Neck Cancers

et al. 2019

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“…This method, however, is only recommended for formalin‐fixed paraffin embedded (FFPE) and resin embedded samples since their tissue morphology are usually very well‐preserved. Recent studies have reported that M2‐polarized macrophages promoted angiogenesis as well as vasculogenesis . Yet on the other hand, there are studies that showed M1‐polarized macrophages to be able to promote angiogenesis as well, secreting VEGF and stimulating endothelial cell sprout formation both in vitro and in vivo .…”

Section: Discussionmentioning

confidence: 99%

Modulating Macrophage Phenotype by Sustained MicroRNA Delivery Improves Host‐Implant Integration

Lin

Mohamed

Lin

et al. 2019

Adv Healthcare Materials

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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.

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“…In this study there was no impact of VEGFR2 knockout on haematopoietic cell populations. An impact of this knockout system on circulatory macrophages and consequent endothelium would be expected to be minimal as there is a very small number of, if any, Tie2-positive, VEGFR2-positive macrophages (Okubo et al 2016).…”

Section: Discussionmentioning

confidence: 99%

Diabetes‐induced microvascular complications at the level of the spinal cord: a contributing factor in diabetic neuropathic pain

Ved

Lobo

Bestall

et al. 2018

The Journal of Physiology

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Key points Diabetes is thought to induce neuropathic pain through activation of dorsal horn sensory neurons in the spinal cord.Here we explore the impact of hyperglycaemia on the blood supply supporting the spinal cord and chronic pain development.In streptozotocin‐induced diabetic rats, neuropathic pain is accompanied by a decline in microvascular integrity in the dorsal horn. Hyperglycaemia‐induced degeneration of the endothelium in the dorsal horn was associated with a loss in vascular endothelial growth factor (VEGF)‐A165b expression. VEGF‐A165b treatment prevented diabetic neuropathic pain and degeneration of the endothelium in the spinal cord.Using an endothelial‐specific VEGFR2 knockout transgenic mouse model, the loss of endothelial VEGFR2 signalling led to a decline in vascular integrity in the dorsal horn and the development of hyperalgesia in VEGFR2 knockout mice.This highlights that vascular degeneration in the spinal cord could be a previously unidentified factor in the development of diabetic neuropathic pain. AbstractAbnormalities of neurovascular interactions within the CNS of diabetic patients is associated with the onset of many neurological disease states. However, to date, the link between the neurovascular network within the spinal cord and regulation of nociception has not been investigated despite neuropathic pain being common in diabetes. We hypothesised that hyperglycaemia‐induced endothelial degeneration in the spinal cord, due to suppression of vascular endothelial growth factor (VEGF)‐A/VEGFR2 signalling, induces diabetic neuropathic pain. Nociceptive pain behaviour was investigated in a chemically induced model of type 1 diabetes (streptozotocin induced, insulin supplemented; either vehicle or VEGF‐A165b treated) and an inducible endothelial knockdown of VEGFR2 (tamoxifen induced). Diabetic animals developed mechanical allodynia and heat hyperalgesia. This was associated with a reduction in the number of blood vessels and reduction in Evans blue extravasation in the lumbar spinal cord of diabetic animals versus age‐matched controls. Endothelial markers occludin, CD31 and VE‐cadherin were downregulated in the spinal cord of the diabetic group versus controls, and there was a concurrent reduction of VEGF‐A165b expression. In diabetic animals, VEGF‐A165b treatment (biweekly i.p., 20 ng g−1) restored normal Evans blue extravasation and prevented vascular degeneration, diabetes‐induced central neuron activation and neuropathic pain. Inducible knockdown of VEGFR2 (tamoxifen treated Tie2CreERT2‐vegfr2flfl mice) led to a reduction in blood vessel network volume in the lumbar spinal cord and development of heat hyperalgesia. These findings indicate that hyperglycaemia leads to a reduction in the VEGF‐A/VEGFR2 signalling cascade, resulting in endothelial dysfunction in the spinal cord, which could be an undiscovered contributing factor to diabetic neuropathic pain.

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M2-polarized macrophages contribute to neovasculogenesis, leading to relapse of oral cancer following radiation

Cited by 81 publications

References 46 publications

Inhibition of EphB4–Ephrin-B2 Signaling Reprograms the Tumor Immune Microenvironment in Head and Neck Cancers

Inhibition of EphB4–Ephrin-B2 Signaling Reprograms the Tumor Immune Microenvironment in Head and Neck Cancers

Modulating Macrophage Phenotype by Sustained MicroRNA Delivery Improves Host‐Implant Integration

Diabetes‐induced microvascular complications at the level of the spinal cord: a contributing factor in diabetic neuropathic pain

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