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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
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 |