Emerging Roles for Eph Receptors and Ephrin Ligands in Immunity

Darling, Thayer K.; Lamb, Tracey J.

doi:10.3389/fimmu.2019.01473

Cited by 170 publications

(167 citation statements)

References 172 publications

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“…Ephrin A is a ligand for Eph A, and both molecules are located on the cell surface [64,65]. The ligand-receptor binding induces bidirectional signals affecting both cells, alters the functions of adhesion molecules [66], and promotes cell-to-cell adhesion, inducing arterio-venous anastomosis [67,68]. Of note, it also produces repulsive forces between the cells to induce axonal guidance [69].…”

Section: Repulsive Moleculesmentioning

confidence: 99%

Promoting Roles of Embryonic Signals in Embryo Implantation and Placentation in Cooperation with Endocrine and Immune Systems

Fujiwara

Ono

Sato

et al. 2020

IJMS

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Embryo implantation in the uterus is an essential process for successful pregnancy in mammals. In general, the endocrine system induces sufficient embryo receptivity in the endometrium, where adhesion-promoting molecules increase and adhesion-inhibitory molecules decrease. Although the precise mechanisms remain unknown, it is widely accepted that maternal–embryo communications, including embryonic signals, improve the receptive ability of the sex steroid hormone-primed endometrium. The embryo may utilize repulsive forces produced by an Eph–ephrin system for its timely attachment to and subsequent invasion through the endometrial epithelial layer. Importantly, the embryonic signals are considered to act on maternal immune cells to induce immune tolerance. They also elicit local inflammation that promotes endometrial differentiation and maternal tissue remodeling during embryo implantation and placentation. Additional clarification of the immune control mechanisms by embryonic signals, such as human chorionic gonadotropin, pre-implantation factor, zona pellucida degradation products, and laeverin, will aid in the further development of immunotherapy to minimize implantation failure in the future.

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Section: Repulsive Moleculesmentioning

confidence: 99%

Promoting Roles of Embryonic Signals in Embryo Implantation and Placentation in Cooperation with Endocrine and Immune Systems

Fujiwara

Ono

Sato

et al. 2020

IJMS

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“…The targeting of multiple receptors in GBM has shown great promise in experimental and preclinical settings [12,46,94]. The overexpression of Eph receptors in GBM has been well documented [95][96][97]. Particularly, EphA2 overexpression has been observed in vascular regions of GBM, indicating its role in tumor neovascularization [38].…”

Section: Discussionmentioning

confidence: 99%

Drug Conjugates for Targeting Eph Receptors in Glioblastoma

et al. 2020

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Glioblastoma (GBM) is a complex and heterogeneous tumor that warrants a comprehensive therapeutic approach for treatment. Tumor-associated antigens offer an opportunity to selectively target various components of the GBM microenvironment while sparing the normal cells within the central nervous system. In this study, we conjugated a multivalent vector protein, QUAD 3.0, that can target four receptors: EphA3, EphA2, EphB2, and also IL-13RA2, spanning virtually 100% of the GBM microenvironment, to doxorubicin derivatives. The conjugates effectively bound to all four receptors, although to varying degrees, and delivered cytotoxic loads to both established and patient-derived GBM cell lines, with IC 50 values in the low nM range. The conjugates were also non-toxic to animals. We anticipate that the QUAD 3.0 Dox conjugates will be further used in preclinical models and possibly clinics in the foreseeable future.Pharmaceuticals 2020, 13, 77 2 of 17 in tumor cells and its microenvironment but not in their normal counterparts. The targeting of such receptors has been achieved in different ways. These include the use of ligand- [11-13], antibody-[14,15], and liposome/nanoparticles-based therapeutic agents [16,17]. Additionally, immunotherapy has utilized antigen-pulsed dendritic cells [18], chimeric antigen receptor T-cells (CAR T-cells) [19][20][21][22], and vaccines [23-25] to selectively target TAA in tumors. While immunotherapy has yet to show clinical benefit in GBM, it is considered a fourth pillar of cancer treatment and holds much promise [26].The Eph receptors represent the largest family of receptor tyrosine kinases. It comprises nine EphA receptors that bind to five ephrinA ligands, and five EphB receptors that bind to three ephrinB ligands. Receptors EphB2 and EphA4 can bind to ephrin ligands of different classes [27]. Their implications have been discovered in various developmental [28,29], physiological [30][31][32], and pathological phenomena [33][34][35]. Moreover, increasing indications of their involvement in tumor invasion, initiation [36], tumor immunity [37], and tumor angiogenesis [12,35] have been observed. Specifically, EphA2 and EphA3 have been shown to be expressed individually in 60% of GBM patients, including in regions of tumor neovasculature, tumor-associated immune cells, and tumor-infiltrating cells [12,35,38]. The increased expression of EphA2 and EphA3 in GBM patients is associated with poor patient prognosis and survival [39,40]. Similarly, the expression of EphB2 has been coupled with increased migration and invasion of GBM cells [41,42].The Eph receptors have been targeted using antibodies, kinase inhibitors, radionucides, and peptides that mimic the receptor ligand and carry a cytotoxic load [10]. The Eph receptors internalize once bound to their ligands and resurface later [12,13]. This allows ligand-based or ligand-mimicking peptide-based therapeutics to be administered in multiple doses given the re-expression of the receptors over time. Recently, an ephrinA5-based cytotoxin that c...

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“…According to both their gene sequence homology and their ligand affinity, Eph receptors are also classified in "A" or "B" subfamilies. In general, Eph-A receptors bind to ephrins-A, and Eph-B to ephrins-B, although Eph-A4 can bind some ephrins-B and Eph-B2 binds ephrin-A5 [33]. A total of 16 Eph receptors (10 Eph-A and 6 Eph-B) and 9 ephrins (6 ephrins-A and 3 ephrins-B) have been described, most of them expressed by mammalian cells, but Eph-A9, Eph-B5, and ephrin-A6 are only present in chicken (Gallus gallus) [34,35].…”

Section: Eph/ephrin Moleculesmentioning

confidence: 99%

Eph/ephrin Signaling and Biology of Mesenchymal Stromal/Stem Cells

Alfaro

Rodriguez-Sosa

Zapata

2020

JCM

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Mesenchymal stromal/stem cells (MSCs) have emerged as important therapeutic agents, owing to their easy isolation and culture, and their remarkable immunomodulatory and anti-inflammatory properties. However, MSCs constitute a heterogeneous cell population which does not express specific cell markers and has important problems for in vivo homing, and factors regulating their survival, proliferation, and differentiation are largely unknown. Accordingly, in the present article, we review the current evidence on the relationships between Eph kinase receptors, their ephrin ligands, and MSCs. These molecules are involved in the adult homeostasis of numerous tissues, and we and other authors have demonstrated their expression in human and murine MSCs derived from both bone marrow and adipose tissue, as well as their involvement in the MSC biology. We extend these studies providing new results on the effects of Eph/ephrins in the differentiation and immunomodulatory properties of MSCs.

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Emerging Roles for Eph Receptors and Ephrin Ligands in Immunity

Cited by 170 publications

References 172 publications

Promoting Roles of Embryonic Signals in Embryo Implantation and Placentation in Cooperation with Endocrine and Immune Systems

Promoting Roles of Embryonic Signals in Embryo Implantation and Placentation in Cooperation with Endocrine and Immune Systems

Drug Conjugates for Targeting Eph Receptors in Glioblastoma

Eph/ephrin Signaling and Biology of Mesenchymal Stromal/Stem Cells

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