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

Apollonio, B. et al. (2023) Tumor-activated lymph node fibroblasts suppress T cell function in diffuse large B cell lymphoma. Journal of Clinical Investigation, 133(13), e166070. (doi: 10.1172/JCI166070) (PMID:37219943) (PMCID:PMC10313378)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Jarrett, Professor Ruth
• Authors: Apollonio, B., Spada, F., Petrov, N., Cozzetto, D., Papazoglou, D., Jarvis, P., Kannambath, S., Terranova-Barberio, M., Amini, R.-M., Enblad, G., Graham, C. E., Benjamin, R., Phillips, E. H., Ellis, R. J., Nuamah, R., Saqi, M., Calado, D. P., Rosenquist, R., Sutton, L. A., Salisbury, J. R., Zacharioudakis, G., Vardi, A., Hagner, P. R., Gandhi, A. K., Bacac, M., Claus, C., Umana, P., Jarrett, R. F., Klein, C., Deutsch, A., and Ramsay, A. G.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: Journal of Clinical Investigation
• Publisher: Americal Society for Clinical Investigation
• ISSN: 0021-9738
• ISSN (Online): 1558-8238
• Published Online: 23 May 2023
• Copyright Holders: Copyright © 2023 Apollonio et al.
• First Published: First published in Journal of Clinical Investigation 133(13): e166070
• Publisher Policy: Reproduced under a Creative Commons License