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The tumor microenvironment is the main source of IL-6 for plasma cell tumor development in mice

Leukemia volume 29, pages 233–237 (2015)Cite this article

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Despite the recent advances in the treatment of blood cancers, the great majority of malignancies of the B-lymphocyte lineage, including CLL, NHL and MM, remain incurable. A key reason for the difficulties to treat B-lineage neoplasms more effectively is the support for tumor cells provided by the tumor microenvironment (TME). Overcoming TME-dependent tumor promotion and disease relapse is thus an important goal of therapy.1 The TME is also a prime target for new approaches to tumor prevention, because it has an important role in neoplastic B cell and plasma cell (PC) development.2 However, strategies to specifically target the TME are often complicated by uncertainty as to whether the tumor-promoting factor considered for molecular targeting is indeed produced by nonmalignant bystander cells, as opposed to tumor cells. In circumstances in which the factor may be generated by both sources, such as interleukin-6 (IL-6) in MM,3,4 we do not know whether the TME-derived portion is critical for myeloma cells and, therefore, worth exploring for new TME-targeted therapies.

We developed an experimental model system to address this issue, using adoptive B cell transfer as the principal research tool. To illustrate the utility of this new method, we evaluated the role of IL-6 in plasma cell tumor (PCT) development in mice. We chose IL-6 because it drives PC neoplasia in both humans and mice and can be produced by both tumor and stromal cells.5 Additionally, despite the early recognition of its critical importance for MM, the promise of IL-6 as a therapeutic target in myeloma has not yet been translated into tangible clinical benefits.6 Here we demonstrate that stromal cell-derived ‘paracrine’ IL-6 is critical for PCT, whereas B cell-derived ‘autocrine’ IL-6 is dispensable. This finding provides proof of principle that the complex pathophysiological interactions of malignant PCs and the TME can be genetically dissected by means of adoptive B cell transfer in mice.

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References

  1. Anderson KC, Carrasco RD . Pathogenesis of myeloma. Annual Rev Pathol 2011; 6: 249–274.

    Article  CAS  Google Scholar 

  2. Rajkumar SV . Preventive strategies in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. Am J Hematol 2012; 87: 453–454.

    Article  PubMed  Google Scholar 

  3. Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwato K et al. Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature 1988; 332: 83–85.

    Article  CAS  PubMed  Google Scholar 

  4. Klein B, Zhang XG, Jourdan M, Content J, Houssiau F, Aarden L et al. Paracrine rather than autocrine regulation of myeloma-cell growth and differentiation by interleukin-6. Blood 1989; 73: 517–526.

    CAS  PubMed  Google Scholar 

  5. Fulciniti M, Hideshima T, Vermot-Desroches C, Pozzi S, Nanjappa P, Shen Z et al. A high-affinity fully human anti-IL-6 mAb, 1339, for the treatment of multiple myeloma. Clin Cancer Res 2009; 15: 7144–7152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chari A, Pri-Chen H, Jagannath S . Complete remission achieved with single agent CNTO 328, an anti-IL-6 monoclonal antibody, in relapsed and refractory myeloma. Clin Lymphoma Myeloma Leuk 2013; 13: 333–337.

    Article  CAS  PubMed  Google Scholar 

  7. Duncan K, Rosean TR, Tompkins VS, Olivier A, Sompallae R, Zhan F et al. (18)F-FDG-PET/CT imaging in an IL-6- and MYC-driven mouse model of human multiple myeloma affords objective evaluation of plasma cell tumor progression and therapeutic response to the proteasome inhibitor ixazomib. Blood Cancer J 2013; 3: e165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Park SS, Shaffer AL, Kim JS, duBois W, Potter M, Staudt LM et al. Insertion of Myc into Igh accelerates peritoneal plasmacytomas in mice. Cancer Res 2005; 65: 7644–7652.

    Article  CAS  PubMed  Google Scholar 

  9. Lattanzio G, Libert C, Aquilina M, Cappelletti M, Ciliberto G, Musiani P et al. Defective development of pristane-oil-induced plasmacytomas in interleukin-6-deficient BALB/c mice. Am J Pathol 1997; 151: 689–696.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Shacter E, Arzadon GK, Williams J . Elevation of interleukin-6 in response to a chronic inflammatory stimulus in mice: inhibition by indomethacin. Blood 1992; 80: 194–202.

    CAS  PubMed  Google Scholar 

  11. Hilbert DM, Migone TS, Kopf M, Leonard WJ, Rudikoff S . Distinct tumorigenic potential of abl and raf in B cell neoplasia: abl activates the IL-6 signaling pathway. Immunity 1996; 5: 81–89.

    Article  CAS  PubMed  Google Scholar 

  12. Hodge LS, Ziesmer SC, Yang ZZ, Secreto FJ, Gertz MA, Novak AJ et al. IL-21 in the bone marrow microenvironment contributes to IgM secretion and proliferation of malignant cells in Waldenstrom macroglobulinemia. Blood 2012; 120: 3774–3782.

    Article  CAS  PubMed  Google Scholar 

  13. Taniguchi K, Karin M . IL-6 and related cytokines as the critical lynchpins between inflammation and cancer. Semin Immunol 2014; 26: 54–74.

    Article  CAS  PubMed  Google Scholar 

  14. Weiss BM, Abadie J, Verma P, Howard RS, Kuehl WM . A monoclonal gammopathy precedes multiple myeloma in most patients. Blood 2009; 113: 5418–5422.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tai YT, Chang BY, Kong SY, Fulciniti M, Yang G, Calle Y et al. Bruton tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma. Blood 2012; 120: 1877–1887.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This research was performed by TRR in partial fulfilment of the requirements for the degree Doctor of Philosophy in the Graduate Immunology Program of the University of Iowa. We thank Kristin Ness for expert mouse husbandry. This work was supported in part by NIH Predoctoral Training Grant 5T32 AI007485 (TRR), by the Intramural Research Program of the NIAID (to HCM), by NCI Core Grant P30CA086862 in support of The University of Iowa Holden Comprehensive Cancer Center, by a Senior Research Award from the Multiple Myeloma Research Foundation (to SJ), by a research award from the International Waldenström’s Macroglobulinemia Foundation (to SJ), by a NCI P50CA097274 career development award (to SJ), and by R01CA151354 from the NCI (to SJ).

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Authors and Affiliations

  1. Interdisciplinary Graduate Program in Immunology, University of Iowa (UI), Iowa City, IA, USA

    T R Rosean, L A Norian, T J Waldschmidt & S Janz

  2. Department of Pathology, UI Carver College of Medicine, Iowa City, IA, USA

    V S Tompkins, A K Olivier, R Sompallae, T J Waldschmidt & S Janz

  3. Bioinformatics Core Facility, UI Carver College of Medicine, Iowa City, IA, USA

    R Sompallae

  4. Department of Urology, UI Carver College of Medicine, Iowa City, IA, USA

    L A Norian

  5. Laboratory of Immunogenetics, NIAID, NIH, Rockville, MD, USA

    H C Morse III

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  1. T R Rosean
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Correspondence to S Janz.

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Rosean, T., Tompkins, V., Olivier, A. et al. The tumor microenvironment is the main source of IL-6 for plasma cell tumor development in mice. Leukemia 29, 233–237 (2015). https://doi.org/10.1038/leu.2014.260

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