Cargando…

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

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 uncl...

Descripción completa

Detalles Bibliográficos
Autores principales: Apollonio, Benedetta, Spada, Filomena, Petrov, Nedyalko, Cozzetto, Domenico, Papazoglou, Despoina, Jarvis, Peter, Kannambath, Shichina, Terranova-Barberio, Manuela, Amini, Rose-Marie, Enblad, Gunilla, Graham, Charlotte, Benjamin, Reuben, Phillips, Elisabeth, Ellis, Richard, Nuamah, Rosamond, Saqi, Mansoor, Calado, Dinis P., Rosenquist, Richard, Sutton, Lesley A., Salisbury, Jon, Zacharioudakis, Georgios, Vardi, Anna, Hagner, Patrick R., Gandhi, Anita K., Bacac, Marina, Claus, Christina, Umana, Pablo, Jarrett, Ruth F., Klein, Christian, Deutsch, Alexander, Ramsay, Alan G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10313378/
https://www.ncbi.nlm.nih.gov/pubmed/37219943
http://dx.doi.org/10.1172/JCI166070
_version_ 1785067114297556992
author Apollonio, Benedetta
Spada, Filomena
Petrov, Nedyalko
Cozzetto, Domenico
Papazoglou, Despoina
Jarvis, Peter
Kannambath, Shichina
Terranova-Barberio, Manuela
Amini, Rose-Marie
Enblad, Gunilla
Graham, Charlotte
Benjamin, Reuben
Phillips, Elisabeth
Ellis, Richard
Nuamah, Rosamond
Saqi, Mansoor
Calado, Dinis P.
Rosenquist, Richard
Sutton, Lesley A.
Salisbury, Jon
Zacharioudakis, Georgios
Vardi, Anna
Hagner, Patrick R.
Gandhi, Anita K.
Bacac, Marina
Claus, Christina
Umana, Pablo
Jarrett, Ruth F.
Klein, Christian
Deutsch, Alexander
Ramsay, Alan G.
author_facet Apollonio, Benedetta
Spada, Filomena
Petrov, Nedyalko
Cozzetto, Domenico
Papazoglou, Despoina
Jarvis, Peter
Kannambath, Shichina
Terranova-Barberio, Manuela
Amini, Rose-Marie
Enblad, Gunilla
Graham, Charlotte
Benjamin, Reuben
Phillips, Elisabeth
Ellis, Richard
Nuamah, Rosamond
Saqi, Mansoor
Calado, Dinis P.
Rosenquist, Richard
Sutton, Lesley A.
Salisbury, Jon
Zacharioudakis, Georgios
Vardi, Anna
Hagner, Patrick R.
Gandhi, Anita K.
Bacac, Marina
Claus, Christina
Umana, Pablo
Jarrett, Ruth F.
Klein, Christian
Deutsch, Alexander
Ramsay, Alan G.
author_sort Apollonio, Benedetta
collection PubMed
description 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.
format Online
Article
Text
id pubmed-10313378
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher American Society for Clinical Investigation
record_format MEDLINE/PubMed
spelling pubmed-103133782023-07-03 Tumor-activated lymph node fibroblasts suppress T cell function in diffuse large B cell lymphoma Apollonio, Benedetta Spada, Filomena Petrov, Nedyalko Cozzetto, Domenico Papazoglou, Despoina Jarvis, Peter Kannambath, Shichina Terranova-Barberio, Manuela Amini, Rose-Marie Enblad, Gunilla Graham, Charlotte Benjamin, Reuben Phillips, Elisabeth Ellis, Richard Nuamah, Rosamond Saqi, Mansoor Calado, Dinis P. Rosenquist, Richard Sutton, Lesley A. Salisbury, Jon Zacharioudakis, Georgios Vardi, Anna Hagner, Patrick R. Gandhi, Anita K. Bacac, Marina Claus, Christina Umana, Pablo Jarrett, Ruth F. Klein, Christian Deutsch, Alexander Ramsay, Alan G. J Clin Invest Research Article 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. American Society for Clinical Investigation 2023-07-03 /pmc/articles/PMC10313378/ /pubmed/37219943 http://dx.doi.org/10.1172/JCI166070 Text en © 2023 Apollonio et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Apollonio, Benedetta
Spada, Filomena
Petrov, Nedyalko
Cozzetto, Domenico
Papazoglou, Despoina
Jarvis, Peter
Kannambath, Shichina
Terranova-Barberio, Manuela
Amini, Rose-Marie
Enblad, Gunilla
Graham, Charlotte
Benjamin, Reuben
Phillips, Elisabeth
Ellis, Richard
Nuamah, Rosamond
Saqi, Mansoor
Calado, Dinis P.
Rosenquist, Richard
Sutton, Lesley A.
Salisbury, Jon
Zacharioudakis, Georgios
Vardi, Anna
Hagner, Patrick R.
Gandhi, Anita K.
Bacac, Marina
Claus, Christina
Umana, Pablo
Jarrett, Ruth F.
Klein, Christian
Deutsch, Alexander
Ramsay, Alan G.
Tumor-activated lymph node fibroblasts suppress T cell function in diffuse large B cell lymphoma
title Tumor-activated lymph node fibroblasts suppress T cell function in diffuse large B cell lymphoma
title_full Tumor-activated lymph node fibroblasts suppress T cell function in diffuse large B cell lymphoma
title_fullStr Tumor-activated lymph node fibroblasts suppress T cell function in diffuse large B cell lymphoma
title_full_unstemmed Tumor-activated lymph node fibroblasts suppress T cell function in diffuse large B cell lymphoma
title_short Tumor-activated lymph node fibroblasts suppress T cell function in diffuse large B cell lymphoma
title_sort tumor-activated lymph node fibroblasts suppress t cell function in diffuse large b cell lymphoma
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10313378/
https://www.ncbi.nlm.nih.gov/pubmed/37219943
http://dx.doi.org/10.1172/JCI166070
work_keys_str_mv AT apolloniobenedetta tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT spadafilomena tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT petrovnedyalko tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT cozzettodomenico tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT papazogloudespoina tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT jarvispeter tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT kannambathshichina tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT terranovabarberiomanuela tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT aminirosemarie tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT enbladgunilla tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT grahamcharlotte tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT benjaminreuben tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT phillipselisabeth tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT ellisrichard tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT nuamahrosamond tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT saqimansoor tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT caladodinisp tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT rosenquistrichard tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT suttonlesleya tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT salisburyjon tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT zacharioudakisgeorgios tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT vardianna tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT hagnerpatrickr tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT gandhianitak tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT bacacmarina tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT clauschristina tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT umanapablo tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT jarrettruthf tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT kleinchristian tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT deutschalexander tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma
AT ramsayalang tumoractivatedlymphnodefibroblastssuppresstcellfunctionindiffuselargebcelllymphoma