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

Autor:	Apollonio B; School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom., Spada F; BRC Advanced Cytometry Platform and., Petrov N; BRC Advanced Cytometry Platform and., Cozzetto D; BRC Translational Bioinformatics at Guy's and St. Thomas's NHS Foundation Trust and King's College London, London, United Kingdom.; Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, United Kingdom., Papazoglou D; School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom., Jarvis P; 5th Surgical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece., Kannambath S; BRC Genomics Research Platform at Guy's and St. Thomas's NHS Foundation Trust and King's College London, London, United Kingdom., Terranova-Barberio M; BRC Advanced Cytometry Platform and., Amini RM; Department of Immunology, Genetics and Pathology, Uppsala University and Hospital, Uppsala, Sweden., Enblad G; Department of Immunology, Genetics and Pathology, Uppsala University and Hospital, Uppsala, Sweden., Graham C; School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom., Benjamin R; School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom., Phillips E; School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom., Ellis R; BRC Advanced Cytometry Platform and., Nuamah R; BRC Genomics Research Platform at Guy's and St. Thomas's NHS Foundation Trust and King's College London, London, United Kingdom., Saqi M; BRC Translational Bioinformatics at Guy's and St. Thomas's NHS Foundation Trust and King's College London, London, United Kingdom., Calado DP; Immunity & Cancer Laboratory, Francis Crick Institute, London, United Kingdom., Rosenquist R; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden., Sutton LA; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden., Salisbury J; Department of Haematology, King's College Hospital NHS Foundation Trust, London, United Kingdom., Zacharioudakis G; 5th Surgical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece., Vardi A; Hematology Department and HCT Unit, G. Papanikolaou Hospital, Thessaloniki, Greece., Hagner PR; Bristol-Myers Squibb, Summit, New Jersey, USA., Gandhi AK; Bristol-Myers Squibb, Summit, New Jersey, USA., Bacac M; Roche Innovation Center Zurich, Schlieren, Switzerland., Claus C; Roche Innovation Center Zurich, Schlieren, Switzerland., Umana P; Roche Innovation Center Zurich, Schlieren, Switzerland., Jarrett RF; MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom., Klein C; Roche Innovation Center Zurich, Schlieren, Switzerland., Deutsch A; Division of Hematology, Medical University of Graz, Graz, Austria., Ramsay AG; School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2023 Jul 03; Vol. 133 (13). Date of Electronic Publication: 2023 Jul 03.
DOI:	10.1172/JCI166070
Abstrakt:	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.
Databáze:	MEDLINE
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