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  • Sun, YiUniv Colorado, Dept Surg, Anschutz Med Campus, Aurora, CO 80045 USA. (author)

Blockade of the CD93 pathway normalizes tumor vasculature to facilitate drug delivery and immunotherapy

  • Article/chapterEnglish2021

Publisher, publication year, extent ...

  • American Association for the Advancement of Science (AAAS),2021
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:uu-451563
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-451563URI
  • https://doi.org/10.1126/scitranslmed.abc8922DOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • The immature and dysfunctional vascular network within solid tumors poses a substantial obstacle to immunotherapy because it creates a hypoxic tumor microenvironment that actively limits immune cell infiltration. The molecular basis underpinning this vascular dysfunction is not fully understood. Using genome-scale receptor array technology, we showed here that insulin-like growth factor binding protein 7 (IGFBP7) interacts with its receptor CD93, and we subsequently demonstrated that this interaction contributes to abnormal tumor vasculature. Both CD93 and IGFBP7 were up-regulated in tumor-associated endothelial cells. IGFBP7 interacted with CD93 via a domain different from multimerin-2, the known ligand for CD93. In two mouse tumor models, blockade of the CD93/IGFBP7 interaction by monoclonal antibodies promoted vascular maturation to reduce leakage, leading to reduced tumor hypoxia and increased tumor perfusion. CD93 blockade in mice increased drug delivery, resulting in an improved antitumor response to gemcitabine or fluorouracil. Blockade of the CD93 pathway triggered a substantial increase in intratumoral effector T cells, thereby sensitizing mouse tumors to immune checkpoint therapy. Last, analysis of samples from patients with cancer under anti-programmed death 1/programmed death-ligand 1 treatment revealed that overexpression of the IGFBP7/CD93 pathway was associated with poor response to therapy. Thus, our study identified a molecular interaction involved in tumor vascular dysfunction and revealed an approach to promote a favorable tumor microenvironment for therapeutic intervention.

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Added entries (persons, corporate bodies, meetings, titles ...)

  • Chen, WeiUniv Colorado, Dept Surg, Anschutz Med Campus, Aurora, CO 80045 USA.;Zhejiang Acad Tradit Chinese Med, Canc Inst Integrated Tradit Chinese & Western Med, Hangzhou 310012, Zhejiang, Peoples R China. (author)
  • Torphy, Robert J.Univ Colorado, Dept Surg, Anschutz Med Campus, Aurora, CO 80045 USA. (author)
  • Yao, ShengYale Univ, Dept Immunobiol, Sch Med, New Haven, CT 06520 USA. (author)
  • Zhu, GefengYale Univ, Dept Immunobiol, Sch Med, New Haven, CT 06520 USA. (author)
  • Lin, RongguiUniv Colorado, Dept Surg, Anschutz Med Campus, Aurora, CO 80045 USA. (author)
  • Lugano, RobertaUppsala universitet,Science for Life Laboratory, SciLifeLab,Vaskulärbiologi(Swepub:uu)roblu911 (author)
  • Miller, Emily N.Univ Colorado, Dept Surg, Anschutz Med Campus, Aurora, CO 80045 USA. (author)
  • Fujiwara, YukiUniv Colorado, Dept Surg, Anschutz Med Campus, Aurora, CO 80045 USA. (author)
  • Bian, LiUniv Colorado, Dept Pathol, Anschutz Med Campus, Aurora, CO 80045 USA. (author)
  • Zheng, LinghuaYale Univ, Dept Immunobiol, Sch Med, New Haven, CT 06520 USA. (author)
  • Anand, SudarshanOregon Hlth & Sci Univ, Dept Cell Dev & Canc Biol, Portland, OR 97239 USA. (author)
  • Gao, FanCALTECH, Caltech Bioinformat Resource Ctr, Beckman Inst, Pasadena, CA 91125 USA. (author)
  • Zhang, WeizhouUniv Florida, Dept Pathol, Gainesville, FL 32610 USA. (author)
  • Ferrara, Sarah E.Univ Colorado, Comprehens Canc Ctr, Aurora, CO 80045 USA. (author)
  • Goodspeed, Andrew E.Univ Colorado, Comprehens Canc Ctr, Aurora, CO 80045 USA.;Univ Colorado, Dept Pharmacol, Anschutz Med Campus, Aurora, CO 80045 USA. (author)
  • Dimberg, AnnaUppsala universitet,Vaskulärbiologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)annadimb (author)
  • Wang, Xiao-JingUniv Colorado, Dept Pathol, Anschutz Med Campus, Aurora, CO 80045 USA.;VA Eastern Colorado Hlth Care Syst, Vet Affairs Med Ctr, Aurora, CO 80045 USA. (author)
  • Edil, Barish H.Univ Oklahoma, Dept Surg, Hlth Sci Ctr, Oklahoma City, OK 73104 USA. (author)
  • Barnett, Carlton C.Univ Colorado, Dept Surg, Anschutz Med Campus, Aurora, CO 80045 USA. (author)
  • Schulick, Richard D.Univ Colorado, Dept Surg, Anschutz Med Campus, Aurora, CO 80045 USA. (author)
  • Chen, LiepingYale Univ, Dept Immunobiol, Sch Med, New Haven, CT 06520 USA. (author)
  • Zhu, YuwenUniv Colorado, Dept Surg, Anschutz Med Campus, Aurora, CO 80045 USA. (author)
  • Univ Colorado, Dept Surg, Anschutz Med Campus, Aurora, CO 80045 USA.Univ Colorado, Dept Surg, Anschutz Med Campus, Aurora, CO 80045 USA.;Zhejiang Acad Tradit Chinese Med, Canc Inst Integrated Tradit Chinese & Western Med, Hangzhou 310012, Zhejiang, Peoples R China. (creator_code:org_t)

Related titles

  • In:Science Translational Medicine: American Association for the Advancement of Science (AAAS)13:6041946-62341946-6242

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