CD70/CD27 signaling promotes the pathogenesis of multiple myeloma and represents a promising therapeutic target

CD70/CD27 signaling promotes the pathogenesis of multiple myeloma and represents a promising therapeutic target

  • Vogelsberg A, Schürch CM, Fend F. Multiples Myelom aus Sicht der Pathologie. Radiologe. 2022;62:12–19.

    Article 
    PubMed 

    Google Scholar
     

  • Kumar SK, Rajkumar V, Kyle RA, van Duin M, Sonneveld P, Mateos MV, et al. Multiple myeloma. Nat Rev Dis Prim. 2017;3:17046.

    Article 
    PubMed 

    Google Scholar
     

  • Forster, S, Radpour, R & Ochsenbein, AF Molecular and immunological mechanisms of clonal evolution in multiple myeloma. Front Immunol 2023;14:1243997.

  • Forster, S & Radpour, R Molecular impact of the tumor microenvironment on multiple myeloma dissemination and extramedullary disease. Front Oncol 2022;12:941437.

  • Thorsteinsdottir S, Dickman PW, Landgren O, Blimark C, Hultcrantz M, Turesson I, et al. Dramatically improved survival in multiple myeloma patients in the recent decade: results from a Swedish population-based study. Haematologica. 2018;103:e412–e415.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • van de Donk NW, Moreau P, Plesner T, Palumbo A, Gay F, Laubach JP, et al. Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma. Blood. 2016;127:681–95.

    Article 
    PubMed 

    Google Scholar
     

  • D’Agostino M, Raje N. Anti-BCMA CAR T-cell therapy in multiple myeloma: can we do better? Leukemia. 2020;34:21–34.

    Article 
    PubMed 

    Google Scholar
     

  • Cohen AD, Garfall AL, Stadtmauer EA, Melenhorst JJ, Lacey SF, Lancaster E, et al. B cell maturation antigen–specific CAR T cells are clinically active in multiple myeloma. J Clin Invest. 2019;129:2210–21.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mailankody S, Devlin SM, Landa J, Nath K, Diamonte C, Carstens EJ, et al. GPRC5D-targeted CAR T cells for myeloma. N Engl J Med. 2022;387:1196–206.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rajkumar SV, Kumar S. Multiple myeloma current treatment algorithms. Blood Cancer J. 2020;10:94.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Raab MS, Podar K, Breitkreutz I, Richardson PG, Anderson KC. Multiple myeloma. Lancet. 2009;374:324–39.

    Article 
    PubMed 

    Google Scholar
     

  • Schürch CM, Rasche L, Frauenfeld L, Weinhold N, Fend F. A review on tumor heterogeneity and evolution in multiple myeloma: pathological, radiological, molecular genetics, and clinical integration. Virchows Arch. 2020;476:337–51.

    Article 
    PubMed 

    Google Scholar
     

  • Hintzen RQ, Lens SM, Koopman G, Pals ST, Spits H, van Lier RA. CD70 represents the human ligand for CD27. Int Immunol. 1994;6:477–80.

    Article 
    PubMed 

    Google Scholar
     

  • Nolte MA, Arens R, van Os R, van Oosterwijk M, Hooibrink B, van Lier RA, et al. Immune activation modulates hematopoiesis through interactions between CD27 and CD70. Nat Immunol. 2005;6:412–8.

    Article 
    PubMed 

    Google Scholar
     

  • Nolte MA, van Olffen RW, van Gisbergen KPJM, van Lier RAW. Timing and tuning of CD27-CD70 interactions: the impact of signal strength in setting the balance between adaptive responses and immunopathology. Immunol Rev. 2009;229:216–31.

    Article 
    PubMed 

    Google Scholar
     

  • Agematsu K, Hokibara S, Nagumo H, Shinozaki K, Yamada S, Komiyama A. Plasma cell generation from B-lymphocytes via CD27/CD70 interaction. Leuk Lymphoma. 1999;35:219–25.

    Article 
    PubMed 

    Google Scholar
     

  • Flieswasser T, Van den Eynde A, Van Audenaerde J, De Waele J, Lardon F, Riether C, et al. The CD70-CD27 axis in oncology: the new kids on the block. J Exp Clin Cancer Res. 2022;41:12.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jacobs J, Deschoolmeester V, Zwaenepoel K, Rolfo C, Silence K, Rottey S, et al. CD70: an emerging target in cancer immunotherapy. Pharmacol Ther. 2015;155:1–10.

    Article 
    PubMed 

    Google Scholar
     

  • Jilaveanu LB, Sznol J, Aziz SA, Duchen D, Kluger HM, Camp RL. CD70 expression patterns in renal cell carcinoma. Hum Pathol. 2012;43:1394–9.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wischhusen J, Jung G, Radovanovic I, Beier C, Steinbach JP, Rimner A, et al. Identification of CD70-mediated apoptosis of immune effector cells as a novel immune escape pathway of human glioblastoma1. Cancer Res. 2002;62:2592–9.

    PubMed 

    Google Scholar
     

  • Pahl JH, Santos SJ, Kuijjer ML, Boerman GH, Sand LG, Szuhai K, et al. Expression of the immune regulation antigen CD70 in osteosarcoma. Cancer Cell Int. 2015;15:31.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Riether C, Schürch CM, Bührer ED, Hinterbrandner M, Huguenin AL, Hoepner S, et al. CD70/CD27 signaling promotes blast stemness and is a viable therapeutic target in acute myeloid leukemia. J Exp Med. 2017;214:359–80.

    Article 
    PubMed 

    Google Scholar
     

  • Ho AW, Hatjiharissi E, Ciccarelli BT, Branagan AR, Hunter ZR, Leleu X, et al. CD27-CD70 interactions in the pathogenesis of Waldenström macroglobulinemia. Blood. 2008;112:4683–9.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • McEarchern JA, Smith LM, McDonagh CF, Klussman K, Gordon KA, Morris-Tilden CA, et al. Preclinical characterization of SGN-70, a humanized antibody directed against CD70. Clin Cancer Res. 2008;14:7763–72.

    Article 
    PubMed 

    Google Scholar
     

  • Zheng W, Liu D, Fan X, Powers L, Goswami M, Hu Y, et al. Potential therapeutic biomarkers in plasma cell myeloma: a flow cytometry study. Cytom Part B Clin Cytom. 2013;84B:222–8.

    Article 

    Google Scholar
     

  • Chu B, Bao L, Wang Y, Lu M, Shi L, Gao S, et al. CD27 antigen negative expression indicates poor prognosis in newly diagnosed multiple myeloma. Clin Immunol. 2020;213:108363.

    Article 
    PubMed 

    Google Scholar
     

  • Katayama Y, Sakai A, Oue N, Asaoku H, Otsuki T, Shiomomura T, et al. A possible role for the loss of CD27-CD70 interaction in myelomagenesis. Br J Haematol. 2003;120:223–34.

    Article 
    PubMed 

    Google Scholar
     

  • Guikema JE, Hovenga S, Vellenga E, Conradie JJ, Abdulahad WH, Bekkema R, et al. CD27 is heterogeneously expressed in multiple myeloma: low CD27 expression in patients with high-risk disease. Br J Haematol. 2003;121:36–43.

    Article 
    PubMed 

    Google Scholar
     

  • Guikema JEJ, Vellenga E, Abdulahad WH, Hovenga S, Bos NA. CD27-triggering on primary plasma cell leukaemia cells has anti-apoptotic effects involving mitogen activated protein kinases. Br J Haematol. 2004;124:299–308.

    Article 
    PubMed 

    Google Scholar
     

  • Kasap C, Izgutdina A, Patiño-Escobar B, Kang AS, Chilakapati N, Akagi N, et al. Targeting high-risk multiple myeloma genotypes with optimized anti-CD70 CAR T cells. Blood. 2025;146:819–33.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, et al. The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012;483:603–7.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kitajima S, Lee KL, Fujioka M, Sun W, You J, Chia GS, et al. Hypoxia-inducible factor-2 alpha up-regulates CD70 under hypoxia and enhances anchorage-independent growth and aggressiveness in cancer cells. Oncotarget. 2018;9:19123–35.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ruf M, Mittmann C, Nowicka AM, Hartmann A, Hermanns T, Poyet C, et al. pVHL/HIF-regulated CD70 expression is associated with infiltration of CD27+ lymphocytes and increased serum levels of soluble CD27 in clear cell renal cell carcinoma. Clin Cancer Res J Am Assoc Cancer Res. 2015;21:889–98.

    Article 

    Google Scholar
     

  • Ryu D, Kim SJ, Hong Y, Jo A, Kim N, Kim HJ, et al. Alterations in the transcriptional programs of myeloma cells and the microenvironment during extramedullary progression affect proliferation and immune evasion. Clin Cancer Res. 2020;26:935–44.

    Article 
    PubMed 

    Google Scholar
     

  • Armour KL, Clark MR, Hadley AG, Williamson LM. Recombinant human IgG molecules lacking Fcγ receptor I binding and monocyte triggering activities. Eur J Immunol. 1999;29:2613–24.

    Article 
    PubMed 

    Google Scholar
     

  • Silence K, Dreier T, Moshir M, Ulrichts P, Gabriels SM, Saunders M, et al. ARGX-110, a highly potent antibody targeting CD70, eliminates tumors via both enhanced ADCC and immune checkpoint blockade. MAbs. 2014;6:523–32.

    Article 
    PubMed 

    Google Scholar
     

  • Morgan GJ, Walker BA, Davies FE. The genetic architecture of multiple myeloma. Nat Rev Cancer. 2012;12:335–48.

    Article 
    PubMed 

    Google Scholar
     

  • Sonugür, FG & Akbulut, H The role of tumor microenvironment in genomic instability of malignant tumors. Front Genet 2019;10:1063.

  • Hu J, Van Valckenborgh E, Menu E, De Bruyne E, Vanderkerken K. Understanding the hypoxic niche of multiple myeloma: therapeutic implications and contributions of mouse models. Dis Model Mech. 2012;5:763–71.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Misund K, Hofste Op Bruinink D, Coward E, Hoogenboezem RM, Rustad EH, Sanders MA, et al. Clonal evolution after treatment pressure in multiple myeloma: heterogenous genomic aberrations and transcriptomic convergence. Leukemia. 2022;36:1887–97.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Flieswasser T, Camara-Clayette V, Danu A, Bosq J, Ribrag V et al. Screening a broad range of solid and haematological tumour types for CD70 expression using a uniform IHC methodology as potential patient stratification method. Cancers 2019;11:1611.

  • McEarchern JA, Oflazoglu E, Francisco L, McDonagh CF, Gordon KA, Stone I, et al. Engineered anti-CD70 antibody with multiple effector functions exhibits in vitro and in vivo antitumor activities. Blood. 2006;109:1185–92.

    Article 
    PubMed 

    Google Scholar
     

  • Riether C, Schürch CM, Flury C, Hinterbrandner M, Drück L, Huguenin AL, et al. Tyrosine kinase inhibitor–induced CD70 expression mediates drug resistance in leukemia stem cells by activating Wnt signaling. Sci Transl Med. 2015;7:298ra119–298ra119.

    Article 
    PubMed 

    Google Scholar
     

  • Bertrand P, Maingonnat C, Penther D, Guney S, Ruminy P, Picquenot JM, et al. The costimulatory molecule CD70 is regulated by distinct molecular mechanisms and is associated with overall survival in diffuse large B-cell lymphoma. Genes, Chromosom Cancer. 2013;52:764–74.

    Article 
    PubMed 

    Google Scholar
     

  • Nakamura K, Sho M, Akahori T, Nishiwada S, Kunishige T, Nakagawa K, et al. Clinical relevance of CD70 expression in resected pancreatic cancer: prognostic value and therapeutic potential. Pancreatology. 2021;21:573–80.

    Article 
    PubMed 

    Google Scholar
     

  • Seyfrid M, Maich WT, Shaikh VM, Tatari N, Upreti D, Piyasena D, et al. CD70 as an actionable immunotherapeutic target in recurrent glioblastoma and its microenvironment. J Immunother Cancer. 2022;10:e003289.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Schurch C, Riether C, Matter MS, Tzankov A, Ochsenbein AF. CD27 signaling on chronic myelogenous leukemia stem cells activates Wnt target genes and promotes disease progression. J Clin Invest. 2012;122:624–38.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ge H, Mu L, Jin L, Yang C, Chang YE, Long Y, et al. Tumor associated CD70 expression is involved in promoting tumor migration and macrophage infiltration in GBM. Int J cancer. 2017;141:1434–44.

    Article 
    PubMed 

    Google Scholar
     

  • Ortiz-Cuaran S, Swalduz A, Foy JP, Marteau S, Morel AP, Fauvet F, et al. Epithelial-to-mesenchymal transition promotes immune escape by inducing CD70 in non-small cell lung cancer. Eur J Cancer. 2022;169:106–22.

    Article 
    PubMed 

    Google Scholar
     

  • Nilsson MB, Yang Y, Heeke S, Patel SA, Poteete A, Udagawa H, et al. CD70 is a therapeutic target upregulated in EMT-associated EGFR tyrosine kinase inhibitor resistance. Cancer Cell. 2023;41:340.e6.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Inaguma S, Lasota J, Czapiewski P, Langfort R, Rys J, Szpor J, et al. CD70 expression correlates with a worse prognosis in malignant pleural mesothelioma patients via immune evasion and enhanced invasiveness. J Pathol. 2020;250:205–16.

    Article 
    PubMed 

    Google Scholar
     

  • Claus C, Riether C, Schürch C, Matter MS, Hilmenyuk T, Ochsenbein AF. CD27 Signaling increases the frequency of regulatory T cells and promotes tumor growth. Cancer Res. 2012;72:3664–76.

    Article 
    PubMed 

    Google Scholar
     

  • Gong L, Luo J, Zhang Y, Yang Y, Li S, Fang X, et al. Nasopharyngeal carcinoma cells promote regulatory T cell development and suppressive activity via CD70-CD27 interaction. Nat Commun. 2023;14:1912.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • van Andel H, Ren Z, Koopmans I, Joosten SP, Kocemba KA, de Lau W, et al. Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins. Proc Natl Acad Sci USA. 2017;114:376–81.

    Article 
    PubMed 

    Google Scholar
     

  • van Andel H, Kocemba KA, Spaargaren M, Pals ST. Aberrant Wnt signaling in multiple myeloma: molecular mechanisms and targeting options. Leukemia. 2019;33:1063–75.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Steinbrunn T, Stühmer T, Sayehli C, Chatterjee M, Einsele H, Bargou RC. Combined targeting of MEK/MAPK and PI3K/Akt signalling in multiple myeloma. Br J Haematol. 2012;159:430–40.

    Article 
    PubMed 

    Google Scholar
     

  • Perroud C, Thurian D, Andres M, Künzi A, Wiedemann G, Zeerleder S, et al. Effect of MAPK activation via mutations in NRAS, KRAS and BRAF on clinical outcome in newly diagnosed multiple myeloma. Hematol Oncol. 2023;41:912–21.

    Article 
    PubMed 

    Google Scholar
     

  • McAvera, R, Quinn, J, Murphy, P & Glavey, S Genetic abnormalities in extramedullary multiple myeloma. Int J Mol Sci 2023;24:11259.

  • Côté S, Lemieux R, Simard C. The survival of IL-6-dependent myeloma cells critically relies on their capability to transit the G1 to S phase interval of the cell cycle. Cell Signal. 2005;17:615–24.

    Article 
    PubMed 

    Google Scholar
     

  • Qiang Y-W, Kopantzev E, Rudikoff S. Insulinlike growth factor–I signaling in multiple myeloma: downstream elements, functional correlates, and pathway cross-talk. Blood. 2002;99:4138–46.

    Article 
    PubMed 

    Google Scholar
     

  • Kawano Y, Kikukawa Y, Fujiwara S, Wada N, Okuno Y, Mitsuya H, et al. Hypoxia reduces CD138 expression and induces an immature and stem cell-like transcriptional program in myeloma cells. Int J Oncol. 2013;43:1809–16.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ikeda S, Tagawa H. Impact of hypoxia on the pathogenesis and therapy resistance in multiple myeloma. Cancer Sci. 2021;112:3995–4004.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Akhmetzyanova I, McCarron MJ, Parekh S, Chesi M, Bergsagel PL, Fooksman DR. Dynamic CD138 surface expression regulates switch between myeloma growth and dissemination. Leukemia. 2020;34:245–56.

    Article 
    PubMed 

    Google Scholar
     

  • Pich C, Sarrabayrouse G, Teiti I, Mariamé B, Rochaix P, Lamant L, et al. Melanoma-expressed CD70 is involved in invasion and metastasis. Br J Cancer. 2016;114:63–70.

    Article 
    PubMed 

    Google Scholar
     

  • Liu L, Yin B, Yi Z, Liu X, Hu Z, Gao W, et al. Breast cancer stem cells characterized by CD70 expression preferentially metastasize to the lungs. Breast Cancer. 2018;25:706–16.

    Article 
    PubMed 

    Google Scholar
     

  • Verkleij CPM, Frerichs KA, Broekmans M, Duetz C, O’Neill CA, Bruins W, et al. NK cell phenotype is associated with response and resistance to daratumumab in relapsed/refractory multiple myeloma. HemaSphere. 2023;7:e881–e881.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Seymour F, Cavenagh JD, Mathews J, Gribben JG. NK cells CD56bright and CD56dim subset cytokine loss and exhaustion is associated with impaired survival in myeloma. Blood Adv. 2022;6:5152–9.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jurisic V, Srdic T, Konjevic G, Markovic O, Colovic M. Clinical stage-depending decrease of NK cell activity in multiple myeloma patients. Med Oncol. 2007;24:312–7.

    Article 
    PubMed 

    Google Scholar
     

  • Riether C, Pabst T, Höpner S, Bacher U, Hinterbrandner M, Banz Y, et al. Targeting CD70 with cusatuzumab eliminates acute myeloid leukemia stem cells in patients treated with hypomethylating agents. Nat Med. 2020;26:1459–67.

    Article 
    PubMed 

    Google Scholar
     

  • Labun K, Montague TG, Krause M, Torres Cleuren YN, Tjeldnes H, Valen E et al.s CHOPCHOP v3: expanding the CRISPR web toolbox beyond genome editing. Nucleic Acids Res. (2019) https://doi.org/10.1093/nar/gkz365.

  • Graf, R, Li, X, Chu, VT & Rajewsky, K sgRNA Sequence motifs blocking efficient CRISPR/Cas9-mediated gene editing. Cell Rep. (2019) https://doi.org/10.1016/j.celrep.2019.01.024.

  • Hu Y, Smyth GK. ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. J Immunol Methods. 2009;347:70–78.

    Article 
    PubMed 

    Google Scholar