Details

Autor(en) / Beteiligte

• Apollonio, Benedetta
• Spada, Filomena
• Petrov, Nedyalko
• Cozzetto, Domenico
• Papazoglou, Despoina
• Jarvis, Peter
• Kannambath, Shichina
• Terranova-Barberio, Manuela
• Amini, Rose-Marie
• Enblad, Gunilla
• Graham, Charlotte
• Benjamin, Reuben
• Phillips, Elisabeth
• Ellis, Richard
• Nuamah, Rosamond
• Saqi, Mansoor
• Calado, Dinis P
• Rosenquist, Richard
• Sutton, Lesley A
• Salisbury, Jon
• Zacharioudakis, Georgios
• Vardi, Anna
• Hagner, Patrick R
• Gandhi, Anita K
• Bacac, Marina
• Claus, Christina
• Umana, Pablo
• Jarrett, Ruth F
• Klein, Christian
• Deutsch, Alexander
• Ramsay, Alan G

Titel

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

Ist Teil von

• The Journal of clinical investigation, 2023-07, Vol.133 (13), p.1-22

Ort / Verlag

United States: American Society for Clinical Investigation

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.