TY - JOUR
T1 - Tumor-activated lymph node fibroblasts suppress T cell function in diffuse large B cell lymphoma
AU - Apollonio, Benedetta
AU - Spada, Filomena
AU - Petrov, Nedyalko
AU - Cozzetto, Domenico
AU - Papazoglou, Despoina
AU - Jarvis, Peter
AU - Kannambath, Shichina
AU - Terranova-Barberio, Manuela
AU - Amini, Rose-Marie
AU - Enblad, Gunilla
AU - Graham, Charlotte E
AU - Benjamin, Reuben
AU - Phillips, Elizabeth H
AU - Ellis, Richard J
AU - Nuamah, Rosamond
AU - Saqi, Mansoor
AU - Calado, Dinis P
AU - Rosenquist, Richard
AU - Sutton, Lesley A
AU - Salisbury, Jonathan R
AU - Zacharioudakis, Georgios
AU - Vardi, Anna
AU - Hagner, Patrick R
AU - Gandhi, Anita K
AU - Bacac, Marina
AU - Claus, Christina
AU - Umana, Pablo
AU - Jarrett, Ruth F
AU - Klein, Christian
AU - Deutsch, Alexander Ja
AU - Ramsay, Alan G
N1 - Funding Information:
This study was supported by Blood Cancer UK (14025 to AGR), the Medical Research Council (MR/N017994/1, project reference 1820702), the British Society of Haematology (to AGR), Cancer Research UK King’s Health Partners Centre at King’s College Lon- don (C604/A25135), and the CRUK City of London Centre Award (CTRQQR-2021/100004). The work also received research support from Roche Glycart AG and Bristol-Myers Squibb as part of research collaborations. This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (CC2078), the UK Medical Research Council (CC2078), and the Wellcome Trust (CC2078). We thank Riccardo Dalla-Favera for providing the IμHABcl6 mouse model. We thank the Nikon Imaging Facility at King’s College London. We would like to thank David Kuo, Brian Fox, and Eric Olson for RNA-Seq bioinformatic analysis; Giulia Morlino for murine tissue support; and Alka Saxena, Pawan Dhami, and Michelle Kleeman for their support at the Flow Cytometry and Genomics Core Facilities. We thank Patricia Ramsay for helpful discussions. We thank the NHS Research Scotland Greater Glasgow and Clyde Biorepository for ethically approved access to lymphoma tissues for this research. This research was also supported by the National Institute for Health and Care Research (NIHR) Biomedical Research Centre based at Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London and/or the NIHR Clinical Research Facility. Figure schematics were created with BioRender.
Publisher Copyright:
© 2023, Apollonio et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2023/7/3
Y1 - 2023/7/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85164211126&partnerID=8YFLogxK
U2 - 10.1172/JCI166070
DO - 10.1172/JCI166070
M3 - Article
C2 - 37219943
SN - 0021-9738
VL - 133
JO - The Journal of clinical investigation
JF - The Journal of clinical investigation
IS - 13
M1 - e166070
ER -
