Advertisement
Original Article Lymphoma/Lymphoproliferative Disorders| Volume 143, ISSUE 1, P124-133.e3, January 2023

Download started.

Ok

Proliferative Tumor-Infiltrating Lymphocytes' Abundance within the Microenvironment Impacts Clinical Outcome in Cutaneous B-Cell Lymphomas

  • Sarah Menguy
    Affiliations
    INSERM U1312, Bordeaux Institute of Oncology, Translational Research on Oncodermatology and Rare Skin Diseases, Bordeaux University, Bordeaux, France

    Pathology Department, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
    Search for articles by this author
  • Martina Prochazkova-Carlotti
    Affiliations
    INSERM U1312, Bordeaux Institute of Oncology, Translational Research on Oncodermatology and Rare Skin Diseases, Bordeaux University, Bordeaux, France
    Search for articles by this author
  • Lamia Azzi-Martin
    Affiliations
    INSERM U1312, Bordeaux Institute of Oncology, Translational Research on Oncodermatology and Rare Skin Diseases, Bordeaux University, Bordeaux, France
    Search for articles by this author
  • Thomas Ferté
    Affiliations
    Department of Public Health, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
    Search for articles by this author
  • Laurence Bresson-Bepoldin
    Affiliations
    INSERM U1312, Bordeaux Institute of Oncology, Translational Research on Oncodermatology and Rare Skin Diseases, Bordeaux University, Bordeaux, France
    Search for articles by this author
  • Christophe Rey
    Affiliations
    Explicyte, Bordeaux, France
    Search for articles by this author
  • Béatrice Vergier
    Affiliations
    INSERM U1312, Bordeaux Institute of Oncology, Translational Research on Oncodermatology and Rare Skin Diseases, Bordeaux University, Bordeaux, France

    Pathology Department, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
    Search for articles by this author
  • Jean-Philippe Merlio
    Affiliations
    INSERM U1312, Bordeaux Institute of Oncology, Translational Research on Oncodermatology and Rare Skin Diseases, Bordeaux University, Bordeaux, France

    Tumor Biology and Tumor Bank Department, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
    Search for articles by this author
  • Marie Beylot-Barry
    Affiliations
    INSERM U1312, Bordeaux Institute of Oncology, Translational Research on Oncodermatology and Rare Skin Diseases, Bordeaux University, Bordeaux, France

    Dermatology Department, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
    Search for articles by this author
  • Anne Pham-Ledard
    Correspondence
    Correspondence: Anne Pham-Ledard, INSERM U1312, Bordeaux Institute of Oncology, Translational Research on Oncodermatology and Rare Skin Diseases, Bordeaux University, Bat 3B, 2ème étage- 146 rue Léo Saignat 33076 Bordeaux, France.
    Affiliations
    INSERM U1312, Bordeaux Institute of Oncology, Translational Research on Oncodermatology and Rare Skin Diseases, Bordeaux University, Bordeaux, France

    Dermatology Department, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
    Search for articles by this author
Published:August 12, 2022DOI:https://doi.org/10.1016/j.jid.2022.06.027
      Primary cutaneous large B-cell lymphoma, leg-type (PCLBCL-LT) is the most aggressive primary cutaneous B-cell lymphoma (PCBCL). Tumor microenvironment has a crucial role in tumor development, and tumor-infiltrating lymphocytes (TILs) can be targeted by immunotherapies. We characterized TILs in 20 PCBCLs to identify the tumor microenvironment features associated with clinical outcomes. We developed a seven‒multiplex immunofluorescence panel using Opal staining and image analysis using HALO software. In PCLBCL-LT, TILs were sparsely intermingled within tumor infiltrate in contrast to those in indolent PCBCL where TILs were scattered around tumor nodule edges with variable tumor infiltration. In PCLBCL-LT, TILs were composed of CD8 and CD4, whereas CD4 was predominant in indolent PCBCL. Proliferative TILs (CD3+Ki-67+ cells) were more abundant in PCLBCL-LT (P = 0.0036) than in indolent PCBCL. In PCLBCL-LT, proliferative TILs' abundance tended to be associated with better progression-free survival. These data were confirmed in a second independent cohort of 23 cases showing that proliferative TILs were more abundant in PCLBCL-LT (P = 0.0205) and that in PCLBCL-LT, high CD3+Ki-67+ cell density was associated with better progression-free survival (P = 0.002). These distinct TILs composition and distribution among PCBCL suggest that proliferative T lymphocytes represent a good prognostic factor in PCLBCL-LT and that stimulating their functions may represent a therapeutic approach.

      Abbreviations:

      ABC-DLBCL (activated B-cell diffuse large B-cell lymphoma), DLBCL (diffuse large B-cell lymphoma), mIF (multiplex immunofluorescence), OS (overall survival), PCBCL (primary cutaneous B-cell lymphoma), PCFCL (primary cutaneous follicle center lymphoma), PCLBCL-LT (primary cutaneous diffuse large B-cell lymphoma, leg type), PFS (progression-free survival), PCMZL (primary cutaneous marginal zone lymphoma), TIL (tumor-infiltrating lymphocyte), TME (tumor microenvironment)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'
      Society Members (SID/ESDR), remember to log in for access.

      Subscribe:

      Subscribe to Journal of Investigative Dermatology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Ansell S.M.
        • Lesokhin A.M.
        • Borrello I.
        • Halwani A.
        • Scott E.C.
        • Gutierrez M.
        • et al.
        PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma.
        N Engl J Med. 2015; 372: 311-319
        • Ansell S.M.
        • Minnema M.C.
        • Johnson P.
        • Timmerman J.M.
        • Armand P.
        • Shipp M.A.
        • et al.
        Nivolumab for relapsed/refractory diffuse large B-cell lymphoma in patients ineligible for or having failed autologous transplantation: a single-arm, phase II study.
        J Clin Oncol. 2019; 37: 481-489
        • Autio M.
        • Leivonen S.K.
        • Brück O.
        • Mustjoki S.
        • Mészáros Jørgensen J.
        • Karjalainen-Lindsberg M.L.
        • et al.
        Immune cell constitution in the tumor microenvironment predicts the outcome in diffuse large B-cell lymphoma.
        Haematologica. 2021; 106: 718-729
        • Barua S.
        • Fang P.
        • Sharma A.
        • Fujimoto J.
        • Wistuba I.
        • Rao A.U.K.
        • et al.
        Spatial interaction of tumor cells and regulatory T cells correlates with survival in non-small cell lung cancer.
        Lung Cancer. 2018; 117: 73-79
        • Carlsen E.D.
        • Swerdlow S.H.
        • Cook J.R.
        • Gibson S.E.
        Class-switched primary cutaneous marginal zone lymphomas are frequently IgG4-positive and have features distinct from IgM-positive cases.
        Am J Surg Pathol. 2019; 43: 1403-1412
        • Chang C.
        • Chen Y.P.
        • Medeiros L.J.
        • Chen T.Y.
        • Chang K.C.
        Higher infiltration of intratumoral CD25+ FOXP3+ lymphocytes correlates with a favorable prognosis in patients with diffuse large B-cell lymphoma.
        Leuk Lymphoma. 2021; 62: 76-85
        • Chang C.
        • Lin C.H.
        • Cheng A.L.
        • Medeiros L.J.
        • Chang K.C.
        Primary central nervous system diffuse large B-cell lymphoma has poorer immune cell infiltration and prognosis than its peripheral counterpart.
        Histopathology. 2015; 67: 625-635
        • Chang K.C.
        • Huang G.C.
        • Jones D.
        • Lin Y.H.
        Distribution patterns of dendritic cells and T cells in diffuse large B-cell lymphomas correlate with prognoses.
        Clin Cancer Res. 2007; 13: 6666-6672
        • Chao J.
        • DeBiasio R.
        • Zhu Z.
        • Giuliano K.A.
        • Schmidt B.F.
        Immunofluorescence signal amplification by the enzyme-catalyzed deposition of a fluorescent reporter substrate (CARD).
        Cytometry. 1996; 23: 48-53
        • Chapuy B.
        • Roemer M.G.M.
        • Stewart C.
        • Tan Y.
        • Abo R.P.
        • Zhang L.
        • et al.
        Targetable genetic features of primary testicular and primary central nervous system lymphomas.
        Blood. 2016; 127: 869-881
        • Chapuy B.
        • Stewart C.
        • Dunford A.J.
        • Kim J.
        • Kamburov A.
        • Redd R.A.
        • et al.
        Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes.
        Nat Med. 2018; 24 ([published corrections appears in Nat Med 2018;24:1292 and Nat Med 2018;24:1290]): 679-690
        • Crowson A.N.
        • Magro C.M.
        • Mihm M.C.
        Prognosticators of melanoma, the melanoma report, and the sentinel lymph node.
        Mod Pathol. 2006; 19: S71-S87
        • Dufva O.
        • Pölönen P.
        • Brück O.
        • Keränen M.A.I.
        • Klievink J.
        • Mehtonen J.
        • et al.
        Immunogenomic landscape of hematological malignancies [published correction appears in Cancer Cell 2020;28:424‒8.
        Cancer Cell. 2020; 38: 380-399.e13
        • Felcht M.
        • Heck M.
        • Weiss C.
        • Becker J.C.
        • Dippel E.
        • Müller C.S.L.
        • et al.
        Expression of the T-cell regulatory marker FOXP3 in primary cutaneous large B-cell lymphoma tumour cells.
        Br J Dermatol. 2012; 167: 348-358
        • Godfrey J.
        • Tumuluru S.
        • Bao R.
        • Leukam M.
        • Venkataraman G.
        • Phillip J.
        • et al.
        PD-L1 gene alterations identify a subset of diffuse large B-cell lymphoma harboring a T-cell-inflamed phenotype.
        Blood. 2019; 133: 2279-2290
        • Hui E.
        • Cheung J.
        • Zhu J.
        • Su X.
        • Taylor M.J.
        • Wallweber H.A.
        • et al.
        T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition.
        Science. 2017; 355: 1428-1433
        • Keir M.E.
        • Butte M.J.
        • Freeman G.J.
        • Sharpe A.H.
        PD-1 and its ligands in tolerance and immunity.
        Annu Rev Immunol. 2008; 26: 677-704
        • Keren L.
        • Bosse M.
        • Marquez D.
        • Angoshtari R.
        • Jain S.
        • Varma S.
        • et al.
        A structured tumor-immune microenvironment in triple negative breast cancer revealed by multiplexed ion beam imaging.
        Cell. 2018; 174 (e19): 1373-1387
        • Kline J.
        • Godfrey J.
        • Ansell S.M.
        The immune landscape and response to immune checkpoint blockade therapy in lymphoma.
        Blood. 2020; 135: 523-533
        • Laurent C.
        • Müller S.
        • Do C.
        • Al-Saati T.
        • Allart S.
        • Larocca L.M.
        • et al.
        Distribution, function, and prognostic value of cytotoxic T lymphocytes in follicular lymphoma: a 3-D tissue-imaging study.
        Blood. 2011; 118: 5371-5379
        • Lee C.W.
        • Ren Y.J.
        • Marella M.
        • Wang M.
        • Hartke J.
        • Couto S.S.
        Multiplex immunofluorescence staining and image analysis assay for diffuse large B cell lymphoma.
        J Immunol Methods. 2020; 478112714
        • Lin L.
        • Couturier J.
        • Yu X.
        • Medina M.A.
        • Kozinetz C.A.
        • Lewis D.E.
        Granzyme B secretion by human memory CD4 T cells is less strictly regulated compared to memory CD8 T cells.
        BMC Immunol. 2014; 15: 36
        • Mareschal S.
        • Pham-Ledard A.
        • Viailly P.J.
        • Dubois S.
        • Bertrand P.
        • Maingonnat C.
        • et al.
        Identification of somatic mutations in primary cutaneous diffuse large B-cell lymphoma, leg type by massive parallel sequencing.
        J Invest Dermatol. 2017; 137: 1984-1994
        • Martínez-Lostao L.
        • Anel A.
        • Pardo J.
        How do cytotoxic lymphocytes kill cancer cells?.
        Clin Cancer Res. 2015; 21: 5047-5056
        • Menguy S.
        • Beylot-Barry M.
        • Parrens M.
        • Ledard A.P.
        • Frison E.
        • Comoz F.
        • et al.
        Primary cutaneous large B-cell lymphomas: relevance of the 2017 World Health Organization classification: clinicopathological and molecular analyses of 64 cases.
        Histopathology. 2019; 74: 1067-1080
        • Menguy S.
        • Prochazkova-Carlotti M.
        • Beylot-Barry M.
        • Saltel F.
        • Vergier B.
        • Merlio J.P.
        • et al.
        PD-L1 and PD-L2 are differentially expressed by macrophages or tumor cells in primary cutaneous diffuse large B-cell lymphoma, leg type.
        Am J Surg Pathol. 2018; 42: 326-334
        • Muris J.J.F.
        • Meijer C.J.L.M.
        • Cillessen S.A.G.M.
        • Vos W.
        • Kummer J.A.
        • Bladergroen B.A.
        • et al.
        Prognostic significance of activated cytotoxic T-lymphocytes in primary nodal diffuse large B-cell lymphomas.
        Leukemia. 2004; 18: 589-596
        • Pham-Ledard A.
        • Cappellen D.
        • Martinez F.
        • Vergier B.
        • Beylot-Barry M.
        • Merlio J.P.
        MYD88 somatic mutation is a genetic feature of primary cutaneous diffuse large B-cell lymphoma, leg type.
        J Invest Dermatol. 2012; 132: 2118-2120
        • Roussel M.
        • Le K.S.
        • Granier C.
        • Llamas Gutierrez F.
        • Foucher E.
        • Le Gallou S.
        • et al.
        Functional characterization of PD1+TIM3+ tumor-infiltrating T cells in DLBCL and effects of PD1 or TIM3 blockade.
        Blood Adv. 2021; 5: 1816-1829
        • Russell J.H.
        • Ley T.J.
        Lymphocyte-mediated cytotoxicity.
        Annu Rev Immunol. 2002; 20: 323-370
        • Saltz J.
        • Gupta R.
        • Hou L.
        • Kurc T.
        • Singh P.
        • Nguyen V.
        • et al.
        Spatial organization and molecular correlation of tumor-infiltrating lymphocytes using deep learning on pathology images.
        Cell Rep. 2018; 23: 181-193.e7
        • Schmitz R.
        • Wright G.W.
        • Huang D.W.
        • Johnson C.A.
        • Phelan J.D.
        • Wang J.Q.
        • et al.
        Genetics and pathogenesis of diffuse large B-cell lymphoma.
        N Engl J Med. 2018; 378: 1396-1407
        • van Gijlswijk R.P.
        • Zijlmans H.J.
        • Wiegant J.
        • Bobrow M.N.
        • Erickson T.J.
        • Adler K.E.
        • et al.
        Fluorochrome-labeled tyramides: use in immunocytochemistry and fluorescence in situ hybridization.
        J Histochem Cytochem. 1997; 45: 375-382
        • Viratham Pulsawatdi A.
        • Craig S.G.
        • Bingham V.
        • McCombe K.
        • Humphries M.P.
        • Senevirathne S.
        • et al.
        A robust multiplex immunofluorescence and digital pathology workflow for the characterisation of the tumour immune microenvironment.
        Mol Oncol. 2020; 14: 2384-2402
        • Willemze R.
        • Cerroni L.
        • Kempf W.
        • Berti E.
        • Facchetti F.
        • Swerdlow S.H.
        • et al.
        The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas [published correction appears in Blood 2019;134:1112].
        Blood. 2019; 133: 1703-1714
        • Wright G.W.
        • Huang D.W.
        • Phelan J.D.
        • Coulibaly Z.A.
        • Roulland S.
        • Young R.M.
        • et al.
        A probabilistic classification tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications.
        Cancer Cell. 2020; 37 (e14): 551-568
        • Zhou X.A.
        • Louissaint Jr., A.
        • Wenzel A.
        • Yang J.
        • Martinez-Escala M.E.
        • Moy A.P.
        • et al.
        Genomic analyses identify recurrent alterations in immune evasion genes in diffuse large B-cell lymphoma, leg type.
        J Invest Dermatol. 2018; 138: 2365‒76