The Journal of Clinical Investigation (Jul 2023)

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 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

Journal volume & issue
Vol. 133, no. 13

Abstract

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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.

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