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

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

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

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.

Original languageEnglish
Article numbere166070
JournalThe Journal of clinical investigation
Volume133
Issue number13
Early online date23 May 2023
DOIs
Publication statusPublished - 3 Jul 2023

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