The Francis Crick Institute
166070.2-20230629151317-covered-e0fd13ba177f913fd3156f593ead4cfd.pdf (31.12 MB)

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

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journal contribution
posted on 2023-07-06, 12:50 authored by Benedetta Apollonio, Filomena Spada, Nedyalko Petrov, Domenico Cozzetto, Despoina Papazoglou, Peter Jarvis, Shichina Kannambath, Manuela Terranova-Barberio, Rose-Marie Amini, Gunilla Enblad, Charlotte Graham, Reuben Benjamin, Elisabeth Phillips, Richard Ellis, Rosamond Nuamah, Mansoor Saqi, Dinis P Calado, Richard Rosenquist, Lesley A Sutton, Jon Salisbury, Georgios Zacharioudakis, Anna Vardi, Patrick R Hagner, Anita K Gandhi, Marina Bacac, Christina Claus, Pablo Umana, Ruth F Jarrett, Christian Klein, Alexander Deutsch, Alan G Ramsay
Recent transcriptomic-based analysis of diffuse large B cell lymphoma (DLBCL) has highlighted the clinical relevance of lymph node (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 identify the presence of an aberrantly remodeled fibroblastic reticular cell (FRC) network, expressing elevated fibroblast activated protein (FAP). RNA-sequencing analyses reveal that exposure to DLBCL reprograms key immunoregulatory pathways in FRCs, including a switch from homeostatic to inflammatory chemokine expression and elevated antigen presentation molecules. Functional assays show that DLBCL-activated FRCs (DLBCL-FRCs) hinder optimal TIL and chimeric antigen receptor T cell (CAR-T) 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 demonstrate the potential to target inhibitory FRCs to rejuvenate interacting TILs. Co-treating organotypic cultures with FAP-targeted immunostimulatory drugs and a bispecific antibody (glofitamab) augmented anti-lymphoma TIL cytotoxicity. Together, our study reveals an immunosuppressive role of FRCs in DLBCL, with implications for immune evasion, disease pathogenesis and optimizing immunotherapy for patients.


Crick (Grant ID: CC2078, Grant title: Calado CC2078)