2. Academic Validation
  3. Tumor-activated lymph node fibroblasts suppress T cell function in diffuse large B cell lymphoma

Tumor-activated lymph node fibroblasts suppress T cell function in diffuse large B cell lymphoma

  • J Clin Invest. 2023 Jul 3;133(13):e166070. doi: 10.1172/JCI166070.
Benedetta Apollonio 1,  Filomena Spada 2,  Nedyalko Petrov 2,  Domenico Cozzetto 3 4,  Despoina Papazoglou 1,  Peter Jarvis 5,  Shichina Kannambath 6,  Manuela Terranova-Barberio 2,  Rose-Marie Amini 7,  Gunilla Enblad 7,  Charlotte Graham 1,  Reuben Benjamin 1,  Elisabeth Phillips 1,  Richard Ellis 2,  Rosamond Nuamah 6,  Mansoor Saqi 3,  Dinis P Calado 8,  Richard Rosenquist 9,  Lesley A Sutton 9,  Jon Salisbury 10,  Georgios Zacharioudakis 5,  Anna Vardi 11,  Patrick R Hagner 12,  Anita K Gandhi 12,  Marina Bacac 13,  Christina Claus 13,  Pablo Umana 13,  Ruth F Jarrett 14,  Christian Klein 13,  Alexander Deutsch 15,  Alan G Ramsay 1
Affiliations

Affiliations

  • 1 School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom.
  • 2 BRC Advanced Cytometry Platform and.
  • 3 BRC Translational Bioinformatics at Guy's and St. Thomas's NHS Foundation Trust and King's College London, London, United Kingdom.
  • 4 Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, United Kingdom.
  • 5 5th Surgical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece.
  • 6 BRC Genomics Research Platform at Guy's and St. Thomas's NHS Foundation Trust and King's College London, London, United Kingdom.
  • 7 Department of Immunology, Genetics and Pathology, Uppsala University and Hospital, Uppsala, Sweden.
  • 8 Immunity & Cancer Laboratory, Francis Crick Institute, London, United Kingdom.
  • 9 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
  • 10 Department of Haematology, King's College Hospital NHS Foundation Trust, London, United Kingdom.
  • 11 Hematology Department and HCT Unit, G. Papanikolaou Hospital, Thessaloniki, Greece.
  • 12 Bristol-Myers Squibb, Summit, New Jersey, USA.
  • 13 Roche Innovation Center Zurich, Schlieren, Switzerland.
  • 14 MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom.
  • 15 Division of Hematology, Medical University of Graz, Graz, Austria.
PMID: 37219943 DOI: 10.1172/JCI166070
Abstract

Recent transcriptomic-based analysis of diffuse large B cell lymphoma (DLBCL) has highlighted the clinical relevance of LN fibroblast and tumor-infiltrating lymphocyte (TIL) signatures within the tumor microenvironment (TME). However, the immunomodulatory role of fibroblasts in lymphoma remains unclear. Here, by studying human and mouse DLBCL-LNs, we identified the presence of an aberrantly remodeled fibroblastic reticular cell (FRC) network expressing elevated fibroblast-activated protein (FAP). RNA-Seq analyses revealed that exposure to DLBCL reprogrammed key immunoregulatory pathways in FRCs, including a switch from homeostatic to inflammatory chemokine expression and elevated antigen-presentation molecules. Functional assays showed that DLBCL-activated FRCs (DLBCL-FRCs) hindered optimal TIL and chimeric antigen receptor (CAR) T cell migration. Moreover, DLBCL-FRCs inhibited CD8+ TIL cytotoxicity in an antigen-specific manner. Notably, the interrogation of patient LNs with imaging mass cytometry identified distinct environments differing in their CD8+ TIL-FRC composition and spatial organization that associated with survival outcomes. We further demonstrated the potential to target inhibitory FRCs to rejuvenate interacting TILs. Cotreating organotypic cultures with FAP-targeted immunostimulatory drugs and a bispecific antibody (glofitamab) augmented antilymphoma TIL cytotoxicity. Our study reveals an immunosuppressive role of FRCs in DLBCL, with implications for immune evasion, disease pathogenesis, and optimizing immunotherapy for patients.

Keywords

Cancer immunotherapy; Immunology; Lymphomas; Oncology.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z