Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Apollonio, B; Spada, F; Petrov, N; Cozzetto, D; Papazoglou, D; Jarvis, P; Kannambath, S; Terranova-Barberio, M; Amini, RM; Enblad, G; Graham, CE; Benjamin, R; Phillips, EH; Ellis, RJ; Nuamah, R; Saqi, M; Calado, DP; Rosenquist, R; Sutton, LA; Salisbury, JR; Zacharioudakis, G; Vardi, A; Hagner, PR; Gandhi, AK; Bacac, M; Claus, C; Umana, P; Jarrett, RF; Klein, C; Deutsch, AJ; Ramsay, AG.
Tumor-activated lymph node fibroblasts suppress T cell function in diffuse large B cell lymphoma.
J Clin Invest. 2023; Doi: 10.1172/JCI166070
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Deutsch Alexander

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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.

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