Tumor-activated lymph node fibroblasts suppress T cell function in diffuse large B cell lymphoma
Benedetta Apollonio, … , Alexander Deutsch, Alan G. Ramsay
Benedetta Apollonio, … , Alexander Deutsch, Alan G. Ramsay
Published May 23, 2023
Citation Information: J Clin Invest. 2023;133(13):e166070. https://doi.org/10.1172/JCI166070.
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Research Article Immunology Oncology

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

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.

Authors

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

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Figure 3

DLBCL-FRCs express elevated CAF marker FAP.

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DLBCL-FRCs express elevated CAF marker FAP. (A) Cell-shape analysis of F...
(A) Cell-shape analysis of FRCs and DLBCL-FRCs(c) (SU-DHL16) treated with isotype or blocking/neutralizing antibodies. Scale bars: 10 μm, Right, quantification. (B) 3D images of FRC and DLBCL-FRC(p) gels stained as indicated. Scale bars: 10 μm. (C) IMC images of rLN (n = 3, same representative tissue presented in Figure 1A) and DLBCL-LNs (n = 53) stained for CD20 (B cells), PDPN (FRCs), and FAP. Scale bars: 100 μm. Frequency of FAP+ FRCs quantified using IMC. (A) Representative data from n = 3 independent experiments. Data are represented as mean ± SEM (A and C). *P < 0.05; **P < 0.01; ****P <.0001, 1-way ANOVA with Tukey’s test (A) or Mann-Whitney U test (C).