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Molecular targets for therapy

Soluble SLAMF7 promotes the growth of myeloma cells via homophilic interaction with surface SLAMF7

Leukemia volume 34, pages 180–195 (2020)Cite this article

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Abstract

SLAMF7 is expressed mainly on multiple myeloma (MM) cells and considered an ideal target for immunotherapeutic approaches. Indeed, elotuzumab, an anti-SLAMF7 antibody, is used for the treatment of MM in combination with immunomodulatory drugs. SLAMF7 is cleaved via unknown mechanisms and detected as a soluble form (sSLAMF7) exclusively in the serum of MM patients; however, little is known about the role of sSLAMF7 in MM biology. In this study, we found that sSLAMF7 enhanced the growth of MM cells via homophilic interaction with surface SLAMF7 and subsequent activation of the SHP-2 and ERK signaling pathways. Elotuzumab suppressed sSLAMF7-induced MM cell growth both in vitro and in vivo. Promoter analyses identified IKZF1 (Ikaros) as a pivotal transcriptional activator of the SLAMF7 gene. Pharmacological targeting of Ikaros by lenalidomide and its analog pomalidomide downregulated SLAMF7 expression and ameliorated the response of MM cells to sSLAMF7. Elotuzumab blocked the growth-promoting function of sSLAMF7 when combined with lenalidomide in a murine xenograft model. Neutralization of sSLAMF7 is a novel antimyeloma mechanism of elotuzumab, which is enhanced by immunomodulatory drugs via downregulation of surface SLAMF7 expression on MM cells. These findings may provide important information for the optimal use of elotuzumab in MM treatment.

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Acknowledgements

We are grateful to Ms Akiko Yonekura and Ms Michiko Ogawa as well as the Core Center of Research Apparatus, Jichi Medical University for technical assistance. This work was supported by the Ministry of Education, Culture, Sports, Science and Technology-supported program for the Strategic Foundation at Private Universities, the Bristol-Myers Squibb Research Grant (to YF), and a Grant-in-Aid for Scientific Research from JSPS (to JK, DK, and YF). JK and YF were funded by the Japan Leukemia Research Fund, Yasuda Memorial Cancer Foundation, Takeda Science Foundation, and Novartis Foundation Japan. JK was also funded by Mitsui Life Social Welfare Foundation and SENSHIN Medical Research Foundation. JK received the Kano Foundation Research Grant and the International Myeloma Foundation Japan’s Grant.

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Authors and Affiliations

  1. Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, 329-0498, Japan

    Jiro Kikuchi, Yoshiaki Kuroda, Daisuke Koyama & Yusuke Furukawa

  2. Department of Hematology, Ibaraki Prefectural Central Hospital, Kasama, Ibaraki, 309-1793, Japan

    Mitsuo Hori

  3. Department of Microbiology, Oita University Faculty of Medicine, Yufu, Oita, 879-5593, Japan

    Hidekatsu Iha

  4. Department of Molecular Immunology and Inflammation, Research Institute, National Center for Global Health and Medicine, Shinjuku, Tokyo, 162-8655, Japan

    Noriko Toyama-Sorimachi

  5. Department of Hematology, Tokyo Women’s Medical University, Shinjuku, Tokyo, 162-8666, Japan

    Shotaro Hagiwara

  6. Division of Hematology, Tochigi Cancer Center, Utsunomiya, Tochigi, 320-0834, Japan

    Tohru Izumi

  7. The Institute of Medical Science, The University of Tokyo, Minato, Tokyo, 108-8639, Japan

    Hiroshi Yasui

  8. Oncology Division, Bristol-Myers Squibb K.K., Shinjuku, Tokyo, 163-1327, Japan

    Atsushi Suzuki

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Contributions

JK, MH and HI performed experiments, analyzed data, and drafted the paper; NTS and SH measured sSLAMF7 in clinical and experimental samples, YK and DK performed experiments; TI and HY provided clinical samples and cell lines; and AS and YF designed and supervised research and finalized the paper. All authors read and approved the paper before submission.

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Correspondence to Yusuke Furukawa.

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This study was funded by Bristol-Myers Squibb K.K. AS is an employee of Bristol-Myers Squibb K.K.

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Kikuchi, J., Hori, M., Iha, H. et al. Soluble SLAMF7 promotes the growth of myeloma cells via homophilic interaction with surface SLAMF7. Leukemia 34, 180–195 (2020). https://doi.org/10.1038/s41375-019-0525-6

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