7n0a: Difference between revisions
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==== | ==Structure of Human Leukaemia Inhibitory Factor with Fab MSC1== | ||
<StructureSection load='7n0a' size='340' side='right'caption='[[7n0a]]' scene=''> | <StructureSection load='7n0a' size='340' side='right'caption='[[7n0a]], [[Resolution|resolution]] 3.10Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br> | <table><tr><td colspan='2'>[[7n0a]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7N0A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7N0A FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7n0a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7n0a OCA], [https://pdbe.org/7n0a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7n0a RCSB], [https://www.ebi.ac.uk/pdbsum/7n0a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7n0a ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7n0a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7n0a OCA], [https://pdbe.org/7n0a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7n0a RCSB], [https://www.ebi.ac.uk/pdbsum/7n0a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7n0a ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/LIF_HUMAN LIF_HUMAN] LIF has the capacity to induce terminal differentiation in leukemic cells. Its activities include the induction of hematopoietic differentiation in normal and myeloid leukemia cells, the induction of neuronal cell differentiation, and the stimulation of acute-phase protein synthesis in hepatocytes. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
PURPOSE: Leukemia inhibitory factor (LIF) is a multifunctional cytokine with numerous reported roles in cancer and is thought to drive tumor development and progression. Characterization of LIF and clinical-stage LIF inhibitors would increase our understanding of LIF as a therapeutic target. EXPERIMENTAL DESIGN: We first tested the association of LIF expression with transcript signatures representing multiple processes regulating tumor development and progression. Next, we developed MSC-1, a high affinity therapeutic antibody that potently inhibits LIF signaling and tested it immune competent animal models of cancer. RESULTS: LIF was associated with signatures of tumor associated macrophages (TAMs) across 7,769 tumor samples spanning 22 solid tumor indications. In human tumors, LIF receptor (LIFR) was highly expressed within the macrophage compartment and LIF treatment drove macrophages to acquire immunosuppressive capacity. MSC-1 potently inhibited LIF signaling by binding an epitope that overlaps with the gp130 receptor binding site on LIF. MSC-1 showed monotherapy efficacy in vivo and drove TAMs to acquire anti-tumor and pro-inflammatory function in syngeneic colon cancer mouse models. Combining MSC-1 with anti-PD1 lead to strong anti-tumor response and a long-term tumor free survival in a significant proportion of treated mice. CONCLUSION: Overall, our findings highlight LIF as a therapeutic target for cancer immunotherapy. | |||
Therapeutic targeting of LIF overcomes macrophage mediated immunosuppression of the local tumor microenvironment.,Hallett R, Bonfill-Teixidor E, Iurlaro R, Arias A, Raman S, Bayliss PE, Egorova O, Neva-Alejo A, McGray AR, Lau E, Bosch A, Beilschmidt M, Maetzel D, Fransson J, Huber-Ruano I, Anido J, Julien JP, Giblin PA, Seoane J Clin Cancer Res. 2022 Nov 28:CCR-21-1888. doi: 10.1158/1078-0432.CCR-21-1888. PMID:36441800<ref>PMID:36441800</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7n0a" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Antibody 3D structures|Antibody 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Bosch A]] | ||
[[Category: Fransson J]] | |||
[[Category: Julien JP]] | |||
[[Category: Raman S]] | |||
Revision as of 13:17, 14 December 2022
Structure of Human Leukaemia Inhibitory Factor with Fab MSC1Structure of Human Leukaemia Inhibitory Factor with Fab MSC1
Structural highlights
FunctionLIF_HUMAN LIF has the capacity to induce terminal differentiation in leukemic cells. Its activities include the induction of hematopoietic differentiation in normal and myeloid leukemia cells, the induction of neuronal cell differentiation, and the stimulation of acute-phase protein synthesis in hepatocytes. Publication Abstract from PubMedPURPOSE: Leukemia inhibitory factor (LIF) is a multifunctional cytokine with numerous reported roles in cancer and is thought to drive tumor development and progression. Characterization of LIF and clinical-stage LIF inhibitors would increase our understanding of LIF as a therapeutic target. EXPERIMENTAL DESIGN: We first tested the association of LIF expression with transcript signatures representing multiple processes regulating tumor development and progression. Next, we developed MSC-1, a high affinity therapeutic antibody that potently inhibits LIF signaling and tested it immune competent animal models of cancer. RESULTS: LIF was associated with signatures of tumor associated macrophages (TAMs) across 7,769 tumor samples spanning 22 solid tumor indications. In human tumors, LIF receptor (LIFR) was highly expressed within the macrophage compartment and LIF treatment drove macrophages to acquire immunosuppressive capacity. MSC-1 potently inhibited LIF signaling by binding an epitope that overlaps with the gp130 receptor binding site on LIF. MSC-1 showed monotherapy efficacy in vivo and drove TAMs to acquire anti-tumor and pro-inflammatory function in syngeneic colon cancer mouse models. Combining MSC-1 with anti-PD1 lead to strong anti-tumor response and a long-term tumor free survival in a significant proportion of treated mice. CONCLUSION: Overall, our findings highlight LIF as a therapeutic target for cancer immunotherapy. Therapeutic targeting of LIF overcomes macrophage mediated immunosuppression of the local tumor microenvironment.,Hallett R, Bonfill-Teixidor E, Iurlaro R, Arias A, Raman S, Bayliss PE, Egorova O, Neva-Alejo A, McGray AR, Lau E, Bosch A, Beilschmidt M, Maetzel D, Fransson J, Huber-Ruano I, Anido J, Julien JP, Giblin PA, Seoane J Clin Cancer Res. 2022 Nov 28:CCR-21-1888. doi: 10.1158/1078-0432.CCR-21-1888. PMID:36441800[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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