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

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Abstract

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.

Authors

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. Salisbury, Georgios Zacharioudakis, Anna Vardi, Patrick R. Hagner, Anita K. Gandhi, Marina Bacac, Christina Claus, Pablo Umana, Ruth F. Jarrett, Christian Klein, Alexander J.A. Deutsch, Alan G. Ramsay