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

Apollonio, Benedetta (author)
Kings Coll London, Fac Life Sci & Med, Sch Canc & Pharmaceut Sci, London, England.;Ist Tumori Giovanni Paolo II, Dept Rare Tumors & Melanoma, Lab Tumor Immunol & Immunotherapy, Viale O Flacco 65, I-70124 Bari, Italy.
Spada, Filomena (author)
Guys & St Thomass NHS Fdn Trust, BRC Adv Cytometry Platform, London, England.
Petrov, Nedyalko (author)
Guys & St Thomass NHS Fdn Trust, BRC Adv Cytometry Platform, London, England.
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Cozzetto, Domenico (author)
Guys & St Thomass NHS Fdn Trust, BRC Translat Bioinformat, London, England.;Kings Coll London, London, England.;Imperial Coll London, Fac Med, Div Digest Dis, London, England.
Papazoglou, Despoina (author)
Kings Coll London, Fac Life Sci & Med, Sch Canc & Pharmaceut Sci, London, England.
Jarvis, Peter (author)
Aristotle Univ Thessaloniki, Surg Dept 5, Thessaloniki, Greece.
Kannambath, Shichina (author)
Kings Coll London, London, England.;Guys & St Thomass NHS Fdn Trust, BRC Genom Res Platform, London, England.
Terranova-Barberio, Manuela (author)
Guys & St Thomass NHS Fdn Trust, BRC Adv Cytometry Platform, London, England.
Amini, Rose-Marie (author)
Uppsala universitet,Institutionen för immunologi, genetik och patologi
Enblad, Gunilla (author)
Uppsala universitet,Institutionen för immunologi, genetik och patologi
Graham, Charlotte (author)
Kings Coll London, Fac Life Sci & Med, Sch Canc & Pharmaceut Sci, London, England.
Benjamin, Reuben (author)
Kings Coll London, Fac Life Sci & Med, Sch Canc & Pharmaceut Sci, London, England.
Phillips, Elisabeth (author)
Kings Coll London, Fac Life Sci & Med, Sch Canc & Pharmaceut Sci, London, England.
Ellis, Richard (author)
Guys & St Thomass NHS Fdn Trust, BRC Adv Cytometry Platform, London, England.
Nuamah, Rosamond (author)
Saqi, Mansoor (author)
Guys & St Thomass NHS Fdn Trust, BRC Translat Bioinformat, London, England.;Kings Coll London, London, England.
Calado, Dinis P. (author)
Francis Crick Inst, Immun & Canc Lab, London, England.
Rosenquist, Richard (author)
Karolinska Institutet
Sutton, Lesley A. (author)
Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
Salisbury, Jon (author)
Kings Coll Hosp NHS Fdn Trust, Dept Haematol, London, England.
Zacharioudakis, Georgios (author)
Aristotle Univ Thessaloniki, Surg Dept 5, Thessaloniki, Greece.
Vardi, Anna (author)
G Papanikolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanikolaou Hosp, HCT Unit, Thessaloniki, Greece.
Hagner, Patrick R. (author)
Bristol Myers Squibb, Summit, NJ USA.
Gandhi, Anita K. (author)
Bristol Myers Squibb, Summit, NJ USA.
Bacac, Marina (author)
Roche Innovat Ctr Zurich, Schlieren, Switzerland.
Claus, Christina (author)
Roche Innovat Ctr Zurich, Schlieren, Switzerland.
Umana, Pablo (author)
Roche Innovat Ctr Zurich, Schlieren, Switzerland.
Jarrett, Ruth F. (author)
Univ Glasgow, MRC, Ctr Virus Res, Glasgow, Scotland.
Klein, Christian (author)
Roche Innovat Ctr Zurich, Schlieren, Switzerland.
Deutsch, Alexander (author)
Med Univ Graz, Div Hematol, Graz, Austria.
Ramsay, Alan G. (author)
Kings Coll London, Fac Life Sci & Med, Sch Canc & Pharmaceut Sci, London, England.;Guys Canc Ctr, Lymphoma Immunol, Innovat Hub, London SE1 9RT, England.
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Kings Coll London, Fac Life Sci & Med, Sch Canc & Pharmaceut Sci, London, England;Ist Tumori Giovanni Paolo II, Dept Rare Tumors & Melanoma, Lab Tumor Immunol & Immunotherapy, Viale O Flacco 65, I-70124 Bari, Italy. Guys & St Thomass NHS Fdn Trust, BRC Adv Cytometry Platform, London, England. (creator_code:org_t)
American Society for Clinical Investigation, 2023
2023
English.
In: Journal of Clinical Investigation. - : American Society for Clinical Investigation. - 0021-9738 .- 1558-8238. ; 133:13
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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 CD'+ TIL cytotoxicity in an antigen-specific manner. Notably, the interrogation of patient LNs with imaging mass cytometry identified distinct environments differing in their CD'+ 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

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