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Article ; Online: Impact of antibody architecture and paratope valency on effector functions of bispecific NKp30 x EGFR natural killer cell engagers.

Boje, Ammelie Svea / Pekar, Lukas / Koep, Katharina / Lipinski, Britta / Rabinovich, Brian / Evers, Andreas / Gehlert, Carina Lynn / Krohn, Steffen / Xiao, Yanping / Krah, Simon / Zaynagetdinov, Rinat / Toleikis, Lars / Poetzsch, Sven / Peipp, Matthias / Zielonka, Stefan / Klausz, Katja

mAbs

2024 Volume 16, Issue 1, Page(s) 2315640

Abstract: Natural killer (NK) cells emerged as a promising effector population that can be harnessed for anti-tumor therapy. In this work, we constructed NK cell engagers (NKCEs) based on NKp30-targeting single domain antibodies (sdAbs) that redirect the cytotoxic ...

Abstract	Natural killer (NK) cells emerged as a promising effector population that can be harnessed for anti-tumor therapy. In this work, we constructed NK cell engagers (NKCEs) based on NKp30-targeting single domain antibodies (sdAbs) that redirect the cytotoxic potential of NK cells toward epidermal growth factor receptor (EGFR)-expressing tumor cells. We investigated the impact of crucial parameters such as sdAb location, binding valencies, the targeted epitope on NKp30, and the overall antibody architecture on the redirection capacity. Our study exploited two NKp30-specific sdAbs, one of which binds a similar epitope on NKp30 as its natural ligand B7-H6, while the other sdAb addresses a non-competing epitope. For EGFR-positive tumor targeting, humanized antigen-binding domains of therapeutic antibody cetuximab were used. We demonstrate that NKCEs bivalently targeting EGFR and bivalently engaging NKp30 are superior to monovalent NKCEs in promoting NK cell-mediated tumor cell lysis and that the architecture of the NKCE can substantially influence killing capacities depending on the NKp30-targeting sdAb utilized. While having a pronounced impact on NK cell killing efficacy, the capabilities of triggering antibody-dependent cellular phagocytosis or complement-dependent cytotoxicity were not significantly affected comparing the bivalent IgG-like NKCEs with cetuximab. However, the fusion of sdAbs can have a slight impact on the NK cell release of immunomodulatory cytokines, as well as on the pharmacokinetic profile of the NKCE due to unfavorable spatial orientation within the molecule architecture. Ultimately, our findings reveal novel insights for the engineering of potent NKCEs triggering the NKp30 axis.
MeSH term(s)	Cetuximab/metabolism ; Epidermal Growth Factor/metabolism ; Binding Sites, Antibody ; Killer Cells, Natural ; ErbB Receptors/metabolism ; Epitopes/metabolism
Chemical Substances	Cetuximab (PQX0D8J21J) ; Epidermal Growth Factor (62229-50-9) ; ErbB Receptors (EC 2.7.10.1) ; Epitopes
Language	English
Publishing date	2024-02-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2537838-7
ISSN	1942-0870 ; 1942-0870
ISSN (online)	1942-0870
ISSN	1942-0870
DOI	10.1080/19420862.2024.2315640
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Article ; Online: Multifunctional NK Cell-Engaging Antibodies Targeting EGFR and NKp30 Elicit Efficient Tumor Cell Killing and Proinflammatory Cytokine Release.

Klausz, Katja / Pekar, Lukas / Boje, Ammelie Svea / Gehlert, Carina Lynn / Krohn, Steffen / Gupta, Tushar / Xiao, Yanping / Krah, Simon / Zaynagetdinov, Rinat / Lipinski, Britta / Toleikis, Lars / Poetzsch, Sven / Rabinovich, Brian / Peipp, Matthias / Zielonka, Stefan

Journal of immunology (Baltimore, Md. : 1950)

2022 Volume 209, Issue 9, Page(s) 1724–1735

Abstract: In this work, we have generated novel Fc-comprising NK cell engagers (NKCEs) that bridge human NKp30 on NK cells to human epidermal growth factor receptor (EGFR) on tumor cells. Camelid-derived VHH single-domain Abs specific for human NKp30 and a ... ...

Abstract	In this work, we have generated novel Fc-comprising NK cell engagers (NKCEs) that bridge human NKp30 on NK cells to human epidermal growth factor receptor (EGFR) on tumor cells. Camelid-derived VHH single-domain Abs specific for human NKp30 and a humanized Fab derived from the EGFR-specific therapeutic Ab cetuximab were used as binding arms. By combining camelid immunization with yeast surface display, we were able to isolate a diverse panel of NKp30-specific VHHs against different epitopes on NKp30. Intriguingly, NKCEs built with VHHs that compete for binding to NKp30 with B7-H6, the natural ligand of NKp30, were significantly more potent in eliciting tumor cell lysis of EGFR-positive tumor cells than NKCEs harboring VHHs that target different epitopes on NKp30 from B7-H6. We demonstrate that the NKCEs can be further improved with respect to killing capabilities by concomitant engagement of FcγRIIIa and that soluble B7-H6 does not impede cytolytic capacities of all scrutinized NKCEs at significantly higher B7-H6 concentrations than observed in cancer patients. Moreover, we show that physiological processes requiring interactions between membrane-bound B7-H6 and NKp30 on NK cells are unaffected by noncompeting NKCEs still eliciting tumor cell killing at low picomolar concentrations. Ultimately, the NKCEs generated in this study were significantly more potent in eliciting NK cell-mediated tumor cell lysis than cetuximab and elicited a robust release of proinflammatory cytokines, both features which might be beneficial for antitumor therapy.
MeSH term(s)	Humans ; B7 Antigens/metabolism ; Cell Death ; Cetuximab/pharmacology ; Cytokines ; Epitopes ; ErbB Receptors ; Killer Cells, Natural ; Ligands ; Natural Cytotoxicity Triggering Receptor 3/metabolism
Chemical Substances	B7 Antigens ; Cetuximab (PQX0D8J21J) ; Cytokines ; EGFR protein, human (EC 2.7.10.1) ; Epitopes ; ErbB Receptors (EC 2.7.10.1) ; Ligands ; Natural Cytotoxicity Triggering Receptor 3 ; NCR3 protein, human
Language	English
Publishing date	2022-09-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.2100970
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Article ; Online: Gas6/MerTK signaling is negatively regulated by NF-κB and supports lung carcinogenesis.

Novitskiy, Sergey V / Zaynagetdinov, Rinat / Vasiukov, Georgii / Gutor, Sergey / Han, Wei / Serezani, Ana / Matafonov, Anton / Gleaves, Linda A / Sherrill, Taylor P / Polosukhin, Vasiliy V / Blackwell, Timothy S

Oncotarget

2019 Volume 10, Issue 66, Page(s) 7031–7042

Abstract: Growth arrest-specific 6 (Gas6) has been implicated in carcinogenesis through activation of its receptors, particularly MerTK. To investigate whether Gas6 plays a role in resistance to NF-κB inhibitors, which have not proven to be effective agents for ... ...

Abstract	Growth arrest-specific 6 (Gas6) has been implicated in carcinogenesis through activation of its receptors, particularly MerTK. To investigate whether Gas6 plays a role in resistance to NF-κB inhibitors, which have not proven to be effective agents for lung cancer therapy, we studied lung cancer models induced by urethane injection or expression of mutant Kras (Kras
Language	English
Publishing date	2019-12-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.27345
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Article: Identification and characterization of M6903, an antagonistic anti-TIM-3 monoclonal antibody.

Zhang, Dong / Jiang, Feng / Zaynagetdinov, Rinat / Huang, Hui / Sood, Vanita D / Wang, Hong / Zhao, Xinyan / Jenkins, Molly H / Ji, Qingyong / Wang, Youbin / Nannemann, David P / Musil, Djordje / Wesolowski, John / Paoletti, Andrea / Bartholomew, Tin / Derner, Melissa G / An, Qi / Iffland, Christel / Halle, Joern-Peter

Oncoimmunology

2020 Volume 9, Issue 1, Page(s) 1744921

Abstract: T cell immunoglobulin and mucin domain-3 (TIM-3) is an immune checkpoint that regulates normal immune responses but can be exploited by tumor cells to evade immune surveillance. TIM-3 is primarily expressed on immune cells, particularly on dysfunctional ... ...

Abstract	T cell immunoglobulin and mucin domain-3 (TIM-3) is an immune checkpoint that regulates normal immune responses but can be exploited by tumor cells to evade immune surveillance. TIM-3 is primarily expressed on immune cells, particularly on dysfunctional and exhausted T cells, and engagement of TIM-3 with its ligands promotes TIM-3-mediated T cell inhibition. Antagonistic ligand-blocking anti-TIM-3 antibodies have the potential to abrogate T cell inhibition, activate antigen-specific T cells, and enhance anti-tumor immunity. Here we describe M6903, a fully human anti-TIM-3 antibody without effector function and with high affinity and selectivity to TIM-3. We demonstrate that M6903 blocks the binding of TIM-3 to three of its ligands, phosphatidylserine (PtdSer), carcinoembryonic antigen cell adhesion-related molecule 1 (CEACAM1), and galectin 9 (Gal-9). These results are supported by an atomic resolution crystal structure and functional assays, which demonstrate that M6903 monotherapy enhanced T cell activation. This activation was further enhanced by the combination of M6903 with bintrafusp alfa, a bifunctional fusion protein that simultaneously blocks the transforming growth factor-β (TGF-β) and programmed death ligand 1 (PD-L1) pathways. M6903 and bintrafusp alfa combination therapy also enhanced anti-tumor efficacy in huTIM-3 knock-in mice, relative to either monotherapy. These in vitro and in vivo data, along with favorable pharmacokinetics in marmoset monkeys, suggest that M6903 as a monotherapy warrants further pre-clinical assessment and that M6903 and bintrafusp alfa may be a promising combination therapy in the clinic.
MeSH term(s)	Animals ; Antibodies, Monoclonal ; Hepatitis A Virus Cellular Receptor 2 ; Lymphocyte Activation ; Mice ; Neoplasms ; T-Lymphocytes
Chemical Substances	Antibodies, Monoclonal ; Hepatitis A Virus Cellular Receptor 2
Language	English
Publishing date	2020-04-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2645309-5
ISSN	2162-402X ; 2162-4011
ISSN (online)	2162-402X
ISSN	2162-4011
DOI	10.1080/2162402X.2020.1744921
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Article ; Online: BMP pathway regulation of and by macrophages.

Talati, Megha / West, James / Zaynagetdinov, Rinat / Hong, Charles C / Han, Wei / Blackwell, Tom / Robinson, Linda / Blackwell, Timothy S / Lane, Kirk

PloS one

2014 Volume 9, Issue 4, Page(s) e94119

Abstract: Pulmonary arterial hypertension (PAH) is a disease of progressively increasing pulmonary vascular resistance, associated with mutations of the type 2 receptor for the BMP pathway, BMPR2. The canonical signaling pathway for BMPR2 is through the SMAD ... ...

Abstract	Pulmonary arterial hypertension (PAH) is a disease of progressively increasing pulmonary vascular resistance, associated with mutations of the type 2 receptor for the BMP pathway, BMPR2. The canonical signaling pathway for BMPR2 is through the SMAD family of transcription factors. BMPR2 is expressed in every cell type, but the impact of BMPR2 mutations affecting SMAD signaling, such as Bmpr2delx4+, had only previously been investigated in smooth muscle and endothelium. In the present study, we created a mouse with universal doxycycline-inducible expression of Bmpr2delx4+ in order to determine if broader expression had an impact relevant to the development of PAH. We found that the most obvious phenotype was a dramatic, but patchy, increase in pulmonary inflammation. We crossed these double transgenic mice onto an NF-κB reporter strain, and by luciferase assays on live mice, individual organs and isolated macrophages, we narrowed down the origin of the inflammatory phenotype to constitutive activation of tissue macrophages. Study of bone marrow-derived macrophages from mutant and wild-type mice suggested a baseline difference in differentiation state in Bmpr2 mutants. When activated with LPS, both mutant and wild-type macrophages secrete BMP pathway inhibitors sufficient to suppress BMP pathway activity in smooth muscle cells (SMC) treated with conditioned media. Functionally, co-culture with macrophages results in a BMP signaling-dependent increase in scratch closure in cultured SMC. We conclude that SMAD signaling through BMP is responsible, in part, for preventing macrophage activation in both live animals and in cells in culture, and that activated macrophages secrete BMP inhibitors in sufficient quantity to cause paracrine effect on vascular smooth muscle.
MeSH term(s)	Animals ; Bone Morphogenetic Protein Receptors, Type II/genetics ; Bone Morphogenetic Protein Receptors, Type II/metabolism ; Cells, Cultured ; Coculture Techniques ; Hypertension, Pulmonary/metabolism ; Hypertension, Pulmonary/physiopathology ; Macrophages/metabolism ; Mice ; Mice, Transgenic ; Muscle, Smooth, Vascular/metabolism ; Myocytes, Smooth Muscle/metabolism ; Signal Transduction/physiology ; Smad Proteins/metabolism
Chemical Substances	Smad Proteins ; Bmpr2 protein, mouse (EC 2.7.11.30) ; Bone Morphogenetic Protein Receptors, Type II (EC 2.7.11.30)
Language	English
Publishing date	2014-04-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0094119
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Article ; Online: Identification of myeloid cell subsets in murine lungs using flow cytometry.

Zaynagetdinov, Rinat / Sherrill, Taylor P / Kendall, Peggy L / Segal, Brahm H / Weller, Kevin P / Tighe, Robert M / Blackwell, Timothy S

American journal of respiratory cell and molecular biology

2013 Volume 49, Issue 2, Page(s) 180–189

Abstract: Although the antibody-based recognition of cell-surface markers has been widely used for the identification of immune cells, overlap in the expression of markers by different cell types and the inconsistent use of antibody panels have resulted in a lack ... ...

Abstract	Although the antibody-based recognition of cell-surface markers has been widely used for the identification of immune cells, overlap in the expression of markers by different cell types and the inconsistent use of antibody panels have resulted in a lack of clearly defined signatures for myeloid cell subsets. We developed a 10-fluorochrome flow cytometry panel for the identification and quantitation of myeloid cells in the lungs, including pulmonary monocytes, myeloid dendritic cells, alveolar and interstitial macrophages, and neutrophils. After the initial sorting of viable CD45(+) leukocytes, we detected three leukocyte subpopulations based on CD68 expression: CD68(-), CD68(low), and CD68(hi). Further characterization of the CD68(hi) population revealed CD45(+)/CD68(hi)/F4/80(+)/CD11b(-)/CD11c(+)/Gr1(-) alveolar macrophages and CD45(+)/CD68(hi)/F4/80(-)/CD11c(+)/Gr1(-)/CD103(+)/major histocompatibility complex (MHC) class II(hi) dendritic cells. The CD68(low) population contained primarily CD45(+)/CD68(low)/F4/80(+)/CD11b(+)/CD11c(+)/Gr1(-)/CD14(low) interstitial macrophages and CD45(+)/CD68(low)/F4/80(+)/CD11b(+)/CD11c(-)/Gr1(low)/CD14(hi) monocytes, whereas the CD68(-) population contained neutrophils (CD45(+)/CD68(-)/F4/80(-)/CD11b(+)/Gr1(hi)). The validity of cellular signatures was confirmed by a morphological analysis of FACS-sorted cells, functional studies, and the depletion of specific macrophage subpopulations using liposomal clodronate. We believe our approach provides an accurate and reproducible method for the isolation, quantification, and characterization of myeloid cell subsets in the lungs, which may be useful for studying the roles of myeloid cells during various pathological processes.
MeSH term(s)	Animals ; Bone Density Conservation Agents/pharmacology ; Clodronic Acid/pharmacology ; Dendritic Cells/cytology ; Dendritic Cells/metabolism ; Flow Cytometry ; Histocompatibility Antigens Class II/metabolism ; Lung/cytology ; Lung/metabolism ; Macrophage Activation/drug effects ; Macrophage Activation/physiology ; Macrophages, Alveolar/cytology ; Macrophages, Alveolar/metabolism ; Mice ; Mice, Transgenic ; Monocytes/cytology ; Monocytes/metabolism
Chemical Substances	Bone Density Conservation Agents ; Histocompatibility Antigens Class II ; Clodronic Acid (0813BZ6866)
Language	English
Publishing date	2013-03-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1025960-0
ISSN	1535-4989 ; 1044-1549
ISSN (online)	1535-4989
ISSN	1044-1549
DOI	10.1165/rcmb.2012-0366MA
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Article: Epithelial-macrophage interactions determine pulmonary fibrosis susceptibility in Hermansky-Pudlak syndrome.

Young, Lisa R / Gulleman, Peter M / Short, Chelsi W / Tanjore, Harikrishna / Sherrill, Taylor / Qi, Aidong / McBride, Andrew P / Zaynagetdinov, Rinat / Benjamin, John T / Lawson, William E / Novitskiy, Sergey V / Blackwell, Timothy S

JCI insight

2016 Volume 1, Issue 17, Page(s) e88947

Abstract: Alveolar epithelial cell (AEC) dysfunction underlies the pathogenesis of pulmonary fibrosis in Hermansky-Pudlak syndrome (HPS) and other genetic syndromes associated with interstitial lung disease; however, mechanisms linking AEC dysfunction and fibrotic ...

Abstract	Alveolar epithelial cell (AEC) dysfunction underlies the pathogenesis of pulmonary fibrosis in Hermansky-Pudlak syndrome (HPS) and other genetic syndromes associated with interstitial lung disease; however, mechanisms linking AEC dysfunction and fibrotic remodeling are incompletely understood. Since increased macrophage recruitment precedes pulmonary fibrosis in HPS, we investigated whether crosstalk between AECs and macrophages determines fibrotic susceptibility. We found that AECs from HPS mice produce excessive MCP-1, which was associated with increased macrophages in the lungs of unchallenged HPS mice. Blocking MCP-1/CCR2 signaling in HPS mice with genetic deficiency of CCR2 or targeted deletion of MCP-1 in AECs normalized macrophage recruitment, decreased AEC apoptosis, and reduced lung fibrosis in these mice following treatment with low-dose bleomycin. We observed increased TGF-β production by HPS macrophages, which was eliminated by CCR2 deletion. Selective deletion of TGF-β in myeloid cells or of TGF-β signaling in AECs through deletion of TGFBR2 protected HPS mice from AEC apoptosis and bleomycin-induced fibrosis. Together, these data reveal a feedback loop in which increased MCP-1 production by dysfunctional AECs results in recruitment and activation of lung macrophages that produce TGF-β, thus amplifying the fibrotic cascade through AEC apoptosis and stimulation of fibrotic remodeling.
MeSH term(s)	Animals ; Bleomycin ; Chemokine CCL2/metabolism ; Disease Susceptibility ; Epithelial Cells/cytology ; Female ; Hermanski-Pudlak Syndrome/immunology ; Macrophages/cytology ; Male ; Mice ; Mice, Inbred C57BL ; Protein-Serine-Threonine Kinases/metabolism ; Pulmonary Alveoli/cytology ; Pulmonary Fibrosis/immunology ; Receptor, Transforming Growth Factor-beta Type II ; Receptors, CCR2/metabolism ; Receptors, Transforming Growth Factor beta/metabolism ; Transforming Growth Factor beta/metabolism
Chemical Substances	Ccl2 protein, mouse ; Ccr2 protein, mouse ; Chemokine CCL2 ; Receptors, CCR2 ; Receptors, Transforming Growth Factor beta ; Transforming Growth Factor beta ; Bleomycin (11056-06-7) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Receptor, Transforming Growth Factor-beta Type II (EC 2.7.11.30)
Language	English
Publishing date	2016-10-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	2379-3708
ISSN	2379-3708
DOI	10.1172/jci.insight.88947
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Article ; Online: Chronic NF-κB activation links COPD and lung cancer through generation of an immunosuppressive microenvironment in the lungs.

Zaynagetdinov, Rinat / Sherrill, Taylor P / Gleaves, Linda A / Hunt, Pierre / Han, Wei / McLoed, Allyson G / Saxon, Jamie A / Tanjore, Harikrishna / Gulleman, Peter M / Young, Lisa R / Blackwell, Timothy S

Oncotarget

2016 Volume 7, Issue 5, Page(s) 5470–5482

Abstract: Nuclear Factor (NF)-κB is positioned to provide the interface between COPD and carcinogenesis through regulation of chronic inflammation in the lungs. Using a tetracycline-inducible transgenic mouse model that conditionally expresses activated IκB kinase ...

Abstract	Nuclear Factor (NF)-κB is positioned to provide the interface between COPD and carcinogenesis through regulation of chronic inflammation in the lungs. Using a tetracycline-inducible transgenic mouse model that conditionally expresses activated IκB kinase β (IKKβ) in airway epithelium (IKTA), we found that sustained NF-κB signaling results in chronic inflammation and emphysema by 4 months. By 11 months of transgene activation, IKTA mice develop lung adenomas. Investigation of lung inflammation in IKTA mice revealed a substantial increase in M2-polarized macrophages and CD4+/CD25+/FoxP3+ regulatory T lymphocytes (Tregs). Depletion of alveolar macrophages in IKTA mice reduced Tregs, increased lung CD8+ lymphocytes, and reduced tumor numbers following treatment with the carcinogen urethane. Alveolar macrophages from IKTA mice supported increased generation of inducible Foxp3+ Tregs ex vivo through expression of TGFβ and IL-10. Targeting of TGFβ and IL-10 reduced the ability of alveolar macrophages from IKTA mice to induce Foxp3 expression on T cells. These studies indicate that sustained activation of NF-κB pathway links COPD and lung cancer through generation and maintenance of a pro-tumorigenic inflammatory environment consisting of alternatively activated macrophages and regulatory T cells.
MeSH term(s)	Animals ; Blotting, Western ; CD8-Positive T-Lymphocytes/immunology ; Cells, Cultured ; Epithelium/immunology ; Female ; Flow Cytometry ; Humans ; I-kappa B Kinase/physiology ; Immunosuppressive Agents/immunology ; Inflammation/immunology ; Interleukin-10/genetics ; Interleukin-10/metabolism ; Lung/immunology ; Lung/metabolism ; Lung/pathology ; Lung Neoplasms/immunology ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Macrophages, Alveolar/immunology ; Male ; Mice ; Mice, Transgenic ; NF-kappa B/genetics ; NF-kappa B/metabolism ; Pulmonary Disease, Chronic Obstructive/immunology ; Pulmonary Disease, Chronic Obstructive/metabolism ; Pulmonary Disease, Chronic Obstructive/pathology ; RNA, Messenger/genetics ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction ; T-Lymphocytes, Regulatory/immunology ; Transforming Growth Factor beta/genetics ; Transforming Growth Factor beta/metabolism
Chemical Substances	Immunosuppressive Agents ; NF-kappa B ; RNA, Messenger ; Transforming Growth Factor beta ; Interleukin-10 (130068-27-8) ; I-kappa B Kinase (EC 2.7.11.10)
Language	English
Publishing date	2016-02-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.6562
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Article: Differential role of the carboxy-terminus of the A(2B) adenosine receptor in stimulation of adenylate cyclase, phospholipase Cbeta, and interleukin-8.

Ryzhov, Sergey / Zaynagetdinov, Rinat / Goldstein, Anna E / Matafonov, Anton / Biaggioni, Italo / Feoktistov, Igor

Purinergic signalling

2009 Volume 5, Issue 3, Page(s) 289–298

Abstract: In human mast cells and microvascular endothelial cells, the A(2B) adenosine receptor controls at least three independent signaling pathways, i.e., Gs-mediated stimulation of adenylate cyclase, Gq-mediated stimulation of phospholipase Cbeta, and Gs/Gq- ... ...

Abstract	In human mast cells and microvascular endothelial cells, the A(2B) adenosine receptor controls at least three independent signaling pathways, i.e., Gs-mediated stimulation of adenylate cyclase, Gq-mediated stimulation of phospholipase Cbeta, and Gs/Gq-independent upregulation of IL-8. Functional analysis of cells transfected with full-length and truncated receptor constructs revealed that the A(2B) receptor C-terminus is important for coupling to Gs and Gq proteins. Removal of the entire cytoplasmic portion in the A(2B) receptor C-terminus rendered it incapable of stimulating adenylate cyclase and phospholipase Cbeta. Conversely, removal of the distal 16 amino acids facilitated signal transduction from the receptor to the downstream Gs but not Gq proteins. However, the A(2B) receptor C-terminus is not essential for upregulation of IL-8. Analysis of chimeric A(2A)/A(2B) receptors demonstrated that only chimeras containing the third intracellular loop of the A(2B) receptor mediated agonist-dependent IL-8 reporter stimulation, suggesting that this domain is important for upregulation of IL-8.
Language	English
Publishing date	2009-01-06
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2172143-9
ISSN	1573-9546 ; 1573-9538
ISSN (online)	1573-9546
ISSN	1573-9538
DOI	10.1007/s11302-008-9129-8
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Article ; Online: Interleukin-5 facilitates lung metastasis by modulating the immune microenvironment.

Zaynagetdinov, Rinat / Sherrill, Taylor P / Gleaves, Linda A / McLoed, Allyson G / Saxon, Jamie A / Habermann, Arun C / Connelly, Linda / Dulek, Daniel / Peebles, R Stokes / Fingleton, Barbara / Yull, Fiona E / Stathopoulos, Georgios T / Blackwell, Timothy S

Cancer research

2015 Volume 75, Issue 8, Page(s) 1624–1634

Abstract: Although the lung is the most common metastatic site for cancer cells, biologic mechanisms regulating lung metastasis are not fully understood. Using heterotopic and intravenous injection models of lung metastasis in mice, we found that IL5, a cytokine ... ...

Abstract	Although the lung is the most common metastatic site for cancer cells, biologic mechanisms regulating lung metastasis are not fully understood. Using heterotopic and intravenous injection models of lung metastasis in mice, we found that IL5, a cytokine involved in allergic and infectious diseases, facilitates metastatic colonization through recruitment of sentinel eosinophils and regulation of other inflammatory/immune cells in the microenvironment of the distal lung. Genetic IL5 deficiency offered marked protection of the lungs from metastasis of different types of tumor cells, including lung cancer, melanoma, and colon cancer. IL5 neutralization protected subjects from metastasis, whereas IL5 reconstitution or adoptive transfer of eosinophils into IL5-deficient mice exerted prometastatic effects. However, IL5 deficiency did not affect the growth of the primary tumor or the size of metastatic lesions. Mechanistic investigations revealed that eosinophils produce CCL22, which recruits regulatory T cells to the lungs. During early stages of metastasis, Treg created a protumorigenic microenvironment, potentially by suppressing IFNγ-producing natural killer cells and M1-polarized macrophages. Together, our results establish a network of allergic inflammatory circuitry that can be co-opted by metastatic cancer cells to facilitate lung colonization, suggesting interventions to target this pathway may offer therapeutic benefits to prevent or treat lung metastasis.
MeSH term(s)	Animals ; Carcinoma, Lewis Lung/genetics ; Carcinoma, Lewis Lung/immunology ; Carcinoma, Lewis Lung/pathology ; Cell Line, Tumor ; Eosinophils/pathology ; Female ; Interleukin-5/physiology ; Lung/immunology ; Lung/pathology ; Lung Neoplasms/genetics ; Lung Neoplasms/immunology ; Lung Neoplasms/secondary ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; T-Lymphocytes, Regulatory/immunology ; Tumor Escape/genetics ; Tumor Microenvironment/genetics ; Tumor Microenvironment/immunology
Chemical Substances	Interleukin-5
Language	English
Publishing date	2015-02-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-14-2379
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Full text online

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