Circulating dendritic cells deficiencies as a new biomarker in classical Hodgkin lymphoma
Corresponding Author
Domenico Galati
Haematology-Oncology and Stem-Cell Transplantation Unit, Department of Haematology and Innovative Therapies, Istituto Nazionale Tumori – IRCCS – Fondazione G. Pascale, Napoli, Italia
Correspondence: Domenico Galati, Haematology-Oncology and Stem-Cell Transplantation Unit, Department of Haematology and Innovative Therapies, Istituto Nazionale Tumori – IRCCS, Fondazione G. Pascale, Via Mariano Semmola, 80131 Napoli, Italy.
E-mail: [email protected]
Search for more papers by this authorSerena Zanotta
Haematology-Oncology and Stem-Cell Transplantation Unit, Department of Haematology and Innovative Therapies, Istituto Nazionale Tumori – IRCCS – Fondazione G. Pascale, Napoli, Italia
Search for more papers by this authorGaetano Corazzelli
Haematology-Oncology and Stem-Cell Transplantation Unit, Department of Haematology and Innovative Therapies, Istituto Nazionale Tumori – IRCCS – Fondazione G. Pascale, Napoli, Italia
Search for more papers by this authorDario Bruzzese
Department of Public Health, Università degli Studi di Napoli Federico II, Napoli, Italia
Search for more papers by this authorGaetana Capobianco
Haematology-Oncology and Stem-Cell Transplantation Unit, Department of Haematology and Innovative Therapies, Istituto Nazionale Tumori – IRCCS – Fondazione G. Pascale, Napoli, Italia
Search for more papers by this authorEmanuela Morelli
Haematology-Oncology and Stem-Cell Transplantation Unit, Department of Haematology and Innovative Therapies, Istituto Nazionale Tumori – IRCCS – Fondazione G. Pascale, Napoli, Italia
Search for more papers by this authorManuela Arcamone
Haematology-Oncology and Stem-Cell Transplantation Unit, Department of Haematology and Innovative Therapies, Istituto Nazionale Tumori – IRCCS – Fondazione G. Pascale, Napoli, Italia
Search for more papers by this authorRosaria De Filippi
Department of Clinical Medicine and Surgery, Università degli Studi di Napoli Federico II, Napoli, Italia
Search for more papers by this authorAntonio Pinto
Haematology-Oncology and Stem-Cell Transplantation Unit, Department of Haematology and Innovative Therapies, Istituto Nazionale Tumori – IRCCS – Fondazione G. Pascale, Napoli, Italia
Search for more papers by this authorCorresponding Author
Domenico Galati
Haematology-Oncology and Stem-Cell Transplantation Unit, Department of Haematology and Innovative Therapies, Istituto Nazionale Tumori – IRCCS – Fondazione G. Pascale, Napoli, Italia
Correspondence: Domenico Galati, Haematology-Oncology and Stem-Cell Transplantation Unit, Department of Haematology and Innovative Therapies, Istituto Nazionale Tumori – IRCCS, Fondazione G. Pascale, Via Mariano Semmola, 80131 Napoli, Italy.
E-mail: [email protected]
Search for more papers by this authorSerena Zanotta
Haematology-Oncology and Stem-Cell Transplantation Unit, Department of Haematology and Innovative Therapies, Istituto Nazionale Tumori – IRCCS – Fondazione G. Pascale, Napoli, Italia
Search for more papers by this authorGaetano Corazzelli
Haematology-Oncology and Stem-Cell Transplantation Unit, Department of Haematology and Innovative Therapies, Istituto Nazionale Tumori – IRCCS – Fondazione G. Pascale, Napoli, Italia
Search for more papers by this authorDario Bruzzese
Department of Public Health, Università degli Studi di Napoli Federico II, Napoli, Italia
Search for more papers by this authorGaetana Capobianco
Haematology-Oncology and Stem-Cell Transplantation Unit, Department of Haematology and Innovative Therapies, Istituto Nazionale Tumori – IRCCS – Fondazione G. Pascale, Napoli, Italia
Search for more papers by this authorEmanuela Morelli
Haematology-Oncology and Stem-Cell Transplantation Unit, Department of Haematology and Innovative Therapies, Istituto Nazionale Tumori – IRCCS – Fondazione G. Pascale, Napoli, Italia
Search for more papers by this authorManuela Arcamone
Haematology-Oncology and Stem-Cell Transplantation Unit, Department of Haematology and Innovative Therapies, Istituto Nazionale Tumori – IRCCS – Fondazione G. Pascale, Napoli, Italia
Search for more papers by this authorRosaria De Filippi
Department of Clinical Medicine and Surgery, Università degli Studi di Napoli Federico II, Napoli, Italia
Search for more papers by this authorAntonio Pinto
Haematology-Oncology and Stem-Cell Transplantation Unit, Department of Haematology and Innovative Therapies, Istituto Nazionale Tumori – IRCCS – Fondazione G. Pascale, Napoli, Italia
Search for more papers by this authorPrevious presentations
Presented in part at the 59th Annual Meeting of the American Society of Haematology, Atlanta, GA, December 9–12, 2017
Summary
No robust biomarkers have been yet validated to identify the recurrence of disease in classical Hodgkin Lymphoma (cHL) patients upon induction treatment. The relevance of the inflammatory microenvironment in cHL prompted us to investigate the key immunomodulator myeloid dendritic cells type-1 (mDC1), type-2 (mDC2) and plasmacytoid dendritic cells (pDC). Blood DC levels were assessed in 52 newly diagnosed patients through multiparametric flow-cytometry. All but two patients received ABVD regimen (doxorubicin, bleomycin, vinblastine, dacarbazine). The median counts of all DC subsets were lower in cHL patients than in healthy controls (P < 0·001). Median mDC counts were inferior for the advanced vs early stage patients for both mDC1s and mDC2s (P = 0·008; P = 0·0007 respectively). Also, median mDC2 counts were reduced in case of bulky (P = 0·0004) and extra-nodal (P = 0·046) disease. Patients with B symptoms had lower levels for mDC1s (P = 0·046), mDC2s (P = 0·009) and pDCs (P = 0·040). All the DC subtypes increased at the end of treatment in 26 patients (P < 0·001): 4·6-fold for mDC1, 2·4-fold for mDC2, 4·5-fold for pDC and aligned DCs subsets with the reference frequencies and the interquartile ranges of the controls. In conclusion, DCs may contribute to the disturbed immunological interplay typical of cHL, prompting a further evaluation of their value as a potential new biomarker.
References
- Abdou, A.G., Asaad, N.Y., Loay, I., Shabaan, M. & Badr, N. (2013) The prognostic role of tumor-associated macrophages and dendritic cells in classic Hodgkin's lymphoma. Journal of Environmental Pathology, Toxicology and Oncology, 32, 289–305.
- Aldinucci, D., Gloghini, A., Pinto, A., De Filippi, R. & Carbone, A. (2010) The classical Hodgkin's lymphoma microenvironment and its role in promoting tumour growth and immune escape. The Journal of Pathology, 221, 248–263.
- Aldinucci, D., Celegato, M. & Casagrande, N. (2016) Microenvironmental interactions in classical Hodgkin lymphoma and their role in promoting tumor growth, immune escape and drug resistance. Cancer Letters, 380, 243–252.
- Bachem, A., Guttler, S., Hartung, E., Ebstein, F., Schaefer, M., Tannert, A., Salama, A., Movassaghi, K., Opitz, C., Mages, H.W., Henn, V., Kloetzel, P.M., Gurka, S. & Kroczek, R.A. (2010) Superior antigen cross-presentation and XCR1 expression define human CD11c+CD141+ cells as homologues of mouse CD8+ dendritic cells. Journal of Experimental Medicine, 207, 1273–1281.
- Banchereau, J., Briere, F., Caux, C., Davoust, J., Lebecque, S., Liu, Y.J., Pulendran, B. & Palucka, K. (2000) Immunobiology of dendritic cells. Annual Review of Immunology, 18, 767–811.
- Boissel, N., Rousselot, P., Raffoux, E., Cayuela, J.M., Maarek, O., Charron, D., Degos, L., Dombret, H., Toubert, A. & Rea, D. (2004) Defective blood dendritic cells in chronic myeloid leukemia correlate with high plasmatic VEGF and are not normalized by imatinib mesylate. Leukemia, 18, 1656–1661.
- Borchmann, P., Haverkamp, H., Lohri, A., Mey, U., Kreissl, S., Greil, R., Markova, J., Feuring-Buske, M., Meissner, J., Duhrsen, U., Ostermann, H., Keller, U., Maschmeyer, G., Kuhnert, G., Dietlein, M., Kobe, C., Eich, H., Baues, C., Stein, H., Fuchs, M., Diehl, V. & Engert, A. (2017) Progression-free survival of early interim PET-positive patients with advanced stage Hodgkin's lymphoma treated with BEACOPPescalated alone or in combination with rituximab (HD18): an open-label, international, randomised phase 3 study by the German Hodgkin Study Group. The Lancet Oncology, 18, 454–463.
- Bourguin-Plonquet, A., Rouard, H., Roudot-Thoraval, F., Bellanger, C., Marquet, J., Delfau-Larue, M.H., Divine, M. & Farcet, J.P. (2002) Severe decrease in peripheral blood dendritic cells in hairy cell leukaemia. British Journal of Haematology, 116, 595–597.
- Brimnes, M.K., Svane, I.M. & Johnsen, H.E. (2006) Impaired functionality and phenotypic profile of dendritic cells from patients with multiple myeloma. Clinical and Experimental Immunology, 144, 76–84.
- Campo, E., Swerdlow, S.H., Harris, N.L., Pileri, S., Stein, H. & Jaffe, E.S. (2011) The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood, 117, 5019–5032.
- Canioni, D., Deau-Fischer, B., Taupin, P., Ribrag, V., Delarue, R., Bosq, J., Rubio, M.T., Roux, D., Vasiliu, V., Varet, B., Brousse, N. & Hermine, O. (2009) Prognostic significance of new immunohistochemical markers in refractory classical Hodgkin lymphoma: a study of 59 cases. PLoS ONE, 4, e6341.
- Chan, C.W. & Housseau, F. (2008) The ‘kiss of death’ by dendritic cells to cancer cells. Cell Death and Differentiation, 15, 58–69.
- Cheson, B.D. (2007) The International Harmonization Project for response criteria in lymphoma clinical trials. Hematology/oncology Clinics of North America, 21, 841–854.
- Cheson, B.D., Horning, S.J., Coiffier, B., Shipp, M.A., Fisher, R.I., Connors, J.M., Lister, T.A., Vose, J., Grillo-Lopez, A., Hagenbeek, A., Cabanillas, F., Klippensten, D., Hiddemann, W., Castellino, R., Harris, N.L., Armitage, J.O., Carter, W., Hoppe, R. & Canellos, G.P. (1999) Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. Journal of Clinical Oncology, 17, 1244.
- Cheson, B.D., Fisher, R.I., Barrington, S.F., Cavalli, F., Schwartz, L.H., Zucca, E. & Lister, T.A. (2014) Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. Journal of Clinical Oncology, 32, 3059–3068.
- Derolf, A.R., Laane, E., Bjorklund, E., Saft, L., Bjorkholm, M. & Porwit, A. (2014) Dendritic cells in bone marrow at diagnosis and after chemotherapy in adult patients with acute myeloid leukaemia. Scandinavian Journal of Immunology, 80, 424–431.
- Dong, R., Cwynarski, K., Entwistle, A., Marelli-Berg, F., Dazzi, F., Simpson, E., Goldman, J.M., Melo, J.V., Lechler, R.I., Bellantuono, I., Ridley, A. & Lombardi, G. (2003) Dendritic cells from CML patients have altered actin organization, reduced antigen processing, and impaired migration. Blood, 101, 3560–3567.
- Fhu, C.W., Graham, A.M., Yap, C.T., Al-Salam, S., Castella, A., Chong, S.M. & Lim, Y.C. (2014) Reed-Sternberg cell-derived lymphotoxin-alpha activates endothelial cells to enhance T-cell recruitment in classical Hodgkin lymphoma. Blood, 124, 2973–2982.
- Franklin, J., Paulus, U., Lieberz, D., Breuer, K., Tesch, H. & Diehl, V. (2000) Is the international prognostic score for advanced stage Hodgkin's disease applicable to early stage patients? German Hodgkin Lymphoma Study Group. Annals of Oncology, 11, 617–623.
- Galati, D., Corazzelli, G., De Filippi, R. & Pinto, A. (2016) Dendritic cells in hematological malignancies. Critical Reviews in Oncology/Hematology, 108, 86–96.
- Hasenclever, D. & Diehl, V. (1998) A prognostic score for advanced Hodgkin's disease. International Prognostic Factors Project on Advanced Hodgkin's Disease. New England Journal of Medicine, 339, 1506–1514.
- Hawkes, E.A., Grigg, A. & Chong, G. (2015) Programmed cell death-1 inhibition in lymphoma. The Lancet Oncology, 16, e234–e245.
- Jongbloed, S.L., Kassianos, A.J., McDonald, K.J., Clark, G.J., Ju, X., Angel, C.E., Chen, C.J., Dunbar, P.R., Wadley, R.B., Jeet, V., Vulink, A.J., Hart, D.N. & Radford, K.J. (2010) Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens. Journal of Experimental Medicine, 207, 1247–1260.
- Josting, A. & Diehl, V. (2001) Early-stage Hodgkin's disease. Current Oncology Reports, 3, 279–284.
- Kuppers, R. (2009) The biology of Hodgkin's lymphoma. Nature Reviews Cancer, 9, 15–27.
- Lister, T.A., Crowther, D., Sutcliffe, S.B., Glatstein, E., Canellos, G.P., Young, R.C., Rosenberg, S.A., Coltman, C.A. & Tubiana, M. (1989) Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. Journal of Clinical Oncology, 7, 1630–1636.
- Maggio, E.M., Van Den Berg, A., Visser, L., Diepstra, A., Kluiver, J., Emmens, R. & Poppema, S. (2002) Common and differential chemokine expression patterns in rs cells of NLP, EBV positive and negative classical Hodgkin lymphomas. International Journal of Cancer, 99, 665–672.
- Mami, N.B., Mohty, M., Chambost, H., Gaugler, B. & Olive, D. (2004) Blood dendritic cells in patients with acute lymphoblastic leukaemia. British Journal of Haematology, 126, 77–80.
- Mohty, M., Isnardon, D., Vey, N., Briere, F., Blaise, D., Olive, D. & Gaugler, B. (2002) Low blood dendritic cells in chronic myeloid leukaemia patients correlates with loss of CD34+/CD38− primitive haematopoietic progenitors. British Journal of Haematology, 119, 115–118.
- Orsini, E., Guarini, A., Chiaretti, S., Mauro, F.R. & Foa, R. (2003) The circulating dendritic cell compartment in patients with chronic lymphocytic leukemia is severely defective and unable to stimulate an effective T-cell response. Cancer Research, 63, 4497–4506.
- R Core Team. (2015) R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria. Available at http://www.R-project.org/
- Ratta, M., Fagnoni, F., Curti, A., Vescovini, R., Sansoni, P., Oliviero, B., Fogli, M., Ferri, E., Della Cuna, G.R., Tura, S., Baccarani, M. & Lemoli, R.M. (2002) Dendritic cells are functionally defective in multiple myeloma: the role of interleukin-6. Blood, 100, 230–237.
- Reizis, B., Bunin, A., Ghosh, H.S., Lewis, K.L. & Sisirak, V. (2011) Plasmacytoid dendritic cells: recent progress and open questions. Annual Review of Immunology, 29, 163–183.
- Roberts, E.W., Broz, M.L., Binnewies, M., Headley, M.B., Nelson, A.E., Wolf, D.M., Kaisho, T., Bogunovic, D., Bhardwaj, N. & Krummel, M.F. (2016) Critical role for CD103(+)/CD141(+) dendritic cells bearing CCR7 for tumor antigen trafficking and priming of T cell immunity in melanoma. Cancer Cell, 30, 324–336.
- Rovati, B., Mariucci, S., Manzoni, M., Bencardino, K. & Danova, M. (2008) Flow cytometric detection of circulating dendritic cells in healthy subjects. European Journal of Histochemistry, 52, 45–52.
- Salmon, H., Idoyaga, J., Rahman, A., Leboeuf, M., Remark, R., Jordan, S., Casanova-Acebes, M., Khudoynazarova, M., Agudo, J., Tung, N., Chakarov, S., Rivera, C., Hogstad, B., Bosenberg, M., Hashimoto, D., Gnjatic, S., Bhardwaj, N., Palucka, A.K., Brown, B.D., Brody, J., Ginhoux, F. & Merad, M. (2016) Expansion and activation of CD103(+) dendritic cell progenitors at the tumor site enhances tumor responses to therapeutic PD-L1 and BRAF inhibition. Immunity, 44, 924–938.
- Scott, D.W. & Gascoyne, R.D. (2014) The tumour microenvironment in B cell lymphomas. Nature Reviews Cancer, 14, 517–534.
- See, P., Dutertre, C.A., Chen, J., Günther, P., McGovern, N., Irac, S.E., Gunawan, M., Beyer, M., Händler, K., Duan, K., Sumatoh, H.R.B., Ruffin, N., Jouve, M., Gea-Mallorqui, E., Hennekam, R.C.M., Lim, T., Yip, C.C., Wen, M., Malleret, B., Low, I., Shadan, N.B., Fen, C.F.S., Tay, A., Lum, J., Zolezzi, F., Larbi, A., Poidinger, M., Chan, J.K.Y., Chen, Q., Renia, L., Haniffa, M., Benaroch, P., Schlitzer, A., Schultze, J.L., Newell, E.W. & Ginhoux, F. (2017) Mapping the human DC lineage through the integration of high-dimensional techniques. Science, 6342, 1016–1038.
- Segura, E. & Villadangos, J.A. (2009) Antigen presentation by dendritic cells in vivo. Current Opinion in Immunology, 21, 105–110.
- Shodell, M., Kempin, S. & Siegal, F.P. (2014) Plasmacytoid dendritic cell and CD4+ T cell deficiencies in untreated Hodgkin disease: implications for susceptibility to opportunistic infections. Leukaemia & Lymphoma, 55, 2656–2657.
- Siegel, R.L., Miller, K.D. & Jemal, A. (2015) Cancer statistics, 2015. CA: A Cancer Journal for Clinicians, 65, 5–29.
- Skoetz, N., Trelle, S., Rancea, M., Haverkamp, H., Diehl, V., Engert, A. & Borchmann, P. (2013) Effect of initial treatment strategy on survival of patients with advanced-stage Hodgkin's lymphoma: a systematic review and network meta-analysis. The Lancet Oncology, 14, 943–952.
- Steidl, C., Lee, T., Shah, S.P., Farinha, P., Han, G., Nayar, T., Delaney, A., Jones, S.J., Iqbal, J., Weisenburger, D.D., Bast, M.A., Rosenwald, A., Muller-Hermelink, H.K., Rimsza, L.M., Campo, E., Delabie, J., Braziel, R.M., Cook, J.R., Tubbs, R.R., Jaffe, E.S., Lenz, G., Connors, J.M., Staudt, L.M., Chan, W.C. & Gascoyne, R.D. (2010) Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. New England Journal of Medicine, 362, 875–885.
- Steidl, C., Connors, J.M. & Gascoyne, R.D. (2011) Molecular pathogenesis of Hodgkin's lymphoma: increasing evidence of the importance of the microenvironment. Journal of Clinical Oncology, 29, 1812–1826.
- Steinman, R.M. (2012) Decisions about dendritic cells: past, present, and future. Annual Review of Immunology, 30, 1–22.
- Steinman, R.M., Adams, J.C. & Cohn, Z.A. (1975) Identification of a novel cell type in peripheral lymphoid organs of mice. IV. Identification and distribution in mouse spleen. Journal of Experimental Medicine, 141, 804–820.
- Tel, J., Smits, E.L., Anguille, S., Joshi, R.N., Figdor, C.G. & de Vries, I.J. (2012) Human plasmacytoid dendritic cells are equipped with antigen-presenting and tumoricidal capacities. Blood, 120, 3936–3944.
- Tudor, C.S., Bruns, H., Daniel, C., Distel, L.V., Hartmann, A., Gerbitz, A. & Buettner, M.J. (2014) Macrophages and dendritic cells as actors in the immune reaction of classical Hodgkin lymphoma. PLoS ONE, 9, e114345.
- Villani, A.C., Satija, R., Reynolds, G., Sarkizova, S., Shekhar, K., Fletcher, J., Griesbeck, M., Butler, A., Zheng, S., Lazo, S., Jardine, L., Dixon, D., Stephenson, E., Nilsson, E., Grundberg, I., McDonald, D., Filby, A., Li, W., De Jager, P.L., Rozenblatt-Rosen, O., Lane, A.A., Haniffa, M., Regev, A. & Hacohen, N. (2017) Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors. Science, 6335, 266–278.
- Wilhelm, T.R., Taddeo, A., Winter, O., Schulz, A.R., Malzer, J.N., Domingo, C., Biesen, R., Alexander, T., Thiel, A., Radbruch, A., Hiepe, F. & Gerl, V. (2016) Siglec-1-positive plasmacytoid dendritic cells (pDCs) in human peripheral blood: a semi-mature and myeloid-like subset imbalanced during protective and autoimmune responses. Clinical Immunology, 163, 42–51.
- Zhang, H., Gregorio, J.D., Iwahori, T., Zhang, X., Choi, O., Tolentino, L.L., Prestwood, T., Carmi, Y. & Engleman, E.G. (2017) A distinct subset of plasmacytoid dendritic cells induces activation and differentiation of B and T lymphocytes. Proceedings of the National Academy of Sciences of United States of America, 114, 1988–1993.
- Ziegler-Heitbrock, L., Ancuta, P., Crowe, S., Dalod, M., Grau, V., Hart, D.N., Leenen, P.J., Liu, Y.J., MacPherson, G., Randolph, G.J., Scherberich, J., Schmitz, J., Shortman, K., Sozzani, S., Strobl, H., Zembala, M., Austyn, J.M. & Lutz, M.B. (2010) Nomenclature of monocytes and dendritic cells in blood. Blood, 116, e74–e80.