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Sökning: WFRF:(Björnstedt M) > (2020-2023) > FPR2 Shapes an Immu...

  • He, FeiDivision of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm (SWE); Department of Urology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou (CHN) (författare)

FPR2 Shapes an Immune-Excluded Pancreatic Tumor Microenvironment and Drives T-cell Exhaustion in a Sex-Dependent Manner

  • Artikel/kapitelEngelska2023

Förlag, utgivningsår, omfång ...

  • 2023-03-15
  • American Association for Cancer Research (AACR),2023
  • printrdacarrier

Nummerbeteckningar

  • LIBRIS-ID:oai:DiVA.org:hv-21403
  • https://urn.kb.se/resolve?urn=urn:nbn:se:hv:diva-21403URI
  • https://doi.org/10.1158/0008-5472.can-22-2932DOI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

Ingår i deldatabas

Klassifikation

  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • Sex-driven immune differences can affect tumor progression and the landscape of the tumor microenvironment. Deeper understanding of these differences in males and females can inform patient selection to improve sex-optimized immunotherapy treatments. In this study, single-cell RNA sequencing and protein analyses uncovered a subpopulation of myeloid cells in pancreatic lesions associated with an immune-excluded tumor phenotype and effector T-cell exhaustion exclusively in females. This myeloid subpopulation was positively correlated with poor survival and genetic signatures of M2-like macrophages and T-cell exhaustion in females. The G-protein coupled receptor formyl peptide receptor 2 (FPR2) mediated these immunosuppressive effects. In vitro, treatment of myeloid cells with a specific FPR2 antagonist prevented exhaustion and enhanced cytotoxicity of effector cells. Proteomic analysis revealed high expression of immunosuppressive secretory proteins PGE2 and galectin-9, enriched integrin pathway, and reduced proinflammatory signals like TNFα and IFNγ in female M2-like macrophages upon FPR2 agonist treatment. In addition, myeloid cells treated with FPR2 agonists induced TIM3 and PD-1 expression only in female T cells. Treatment with anti-TIM3 antibodies reversed T-cell exhaustion and stimulated their ability to infiltrate and kill pancreatic spheroids. In vivo, progression of syngeneic pancreatic tumors was significantly suppressed in FPR2 knockout (KO) female mice compared with wild-type (WT) female mice and to WT and FPR2 KO male mice. In female mice, inoculation of tumors with FPR2 KO macrophages significantly reduced tumor growth compared with WT macrophages. Overall, this study identified an immunosuppressive function of FPR2 in females, highlighting a potential sex-specific precision immunotherapy strategy.

Ämnesord och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Tay, Apple H.M.Department of Biological Science, Nanyang Technological University, Singapore (SGP); Department of Oncology–Pathology, Karolinska Institute, Stockholm(SWE) (författare)
  • Calandigary, AhmedDepartment of Immunology, Genetics, and Pathology, Clinical Immunology, Uppsala (SWE) (författare)
  • Malki, EnanaDivision of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm (SWE) (författare)
  • Suzuki, SayakaDivision of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm (SWE) (författare)
  • Liu, TianjieDepartment of Urology, First affiliated hospital of Xi'an Jiaotong university, Xi'an, Shaanxi (CHN) (författare)
  • Wang, QiDepartment of Urology, First affiliated hospital of Xi'an Jiaotong university, Xi'an, Shaanxi (CHN) (författare)
  • Fernández-Moro, CarlosDivision of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm (SWE) (författare)
  • Kaisso, MarinaDivision of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm (SWE) (författare)
  • Olofsson-Sahl, PeterHögskolan Väst,Grants and Innovation Office (GIO),Pronoxis AB, Medicon Village, Lund (SWE)(Swepub:hv)u050742 (författare)
  • Melssen, MaritDepartment of Immunology, Genetics and Pathology, Vascular Biology, Uppsala (SWE) (författare)
  • Sze, Siu KwanDepartment of Biological Science, Nanyang Technological University, Singapore (SGP); Department of Health Sciences, Faculty of Applied Health Sciences, Brock University, Ontario (CAN) (författare)
  • Björnstedt, MikaelDivision of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm (SWE) (författare)
  • Löhr, Matthias J.Department of Clinical Science, Intervention and Technology, Pancreatic Cancer Research Laboratory, Karolinska Institutet, Stockholm (SWE) (författare)
  • Karlsson, Mikael C.I.Department of Microbiology, Tumor and Cell Biology, Karolinska Insitutet, Stockholm (SWE) (författare)
  • Heuchel, RainerDepartment of Clinical Science, Intervention and Technology, Pancreatic Cancer Research Laboratory, Karolinska Institutet, Stockholm (SWE) (författare)
  • Sarhan, DhifafDivision of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm (SWE) (författare)
  • Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm (SWE); Department of Urology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou (CHN)Department of Biological Science, Nanyang Technological University, Singapore (SGP); Department of Oncology–Pathology, Karolinska Institute, Stockholm(SWE) (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:Cancer Research: American Association for Cancer Research (AACR)83:10, s. 1628-16450008-54721538-7445

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