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Mechanisms of resistance

Bone marrow stromal cell-mediated degradation of CD20 leads to primary rituximab resistance in mantle cell lymphoma

Leukemia volume 35, pages 1506–1510 (2021)Cite this article

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The CD20 antigen is an ideal target of immunotherapy because of its stable and uniform expression among B-cell non-Hodgkin lymphomas (NHL). In fact, monoclonal antibodies targeting CD20 have greatly changed the therapeutic landscape of B-cell malignancies, especially indolent lymphomas including mantle cell lymphoma (MCL) [1]. Resistance to the first-in-class CD20 antibody rituximab is not frequent but is an extremely important clinical issue. Although several mechanisms have been proposed [2], loss of CD20 expression is undoubtedly one of the most straightforward and common causes of rituximab resistance. Previous studies have implicated epigenetic silencing [3], CD20 gene mutations [4], and trogocytosis by phagocytes [5] as mechanisms underlying CD20 downregulation. Here, we report autophagic degradation of CD20 as a novel mechanism of rituximab resistance.

In summary, this study uncovered a novel mechanism of CD20 downregulation leading to innate resistance to rituximab (Supplementary Fig. S4). The BMSC-mediated chemoresistance could be overcome via inhibition of protective autophagy, for example, using an anti-interleukin-6 antibody, as suggested by a recent independent study [15].

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Fig. 1: Interaction with BMSCs is associated with CD20 downregulation and rituximab resistance in MCL cells.
Fig. 2: Bone marrow stromal cells promote CD20 degradation via induction of selective autophagy.

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Acknowledgements

The authors are indebted to Drs. Martin J.S. Dyer (Leicester University, Leicester, UK), Yuichi Nakamura (Saitama Medical University, Saitama, Japan), Akihiro Umezawa (National Research Institute for Child Health and Development, Tokyo, Japan), Hirofumi Hamada (Sapporo Medical University, Sapporo, Japan), and Yong Sung Choi (Ochsner Clinic Foundation, New Orleans, LA) for providing cell lines (see “Materials and Methods” in Supplementary Information for details). We are grateful to Ms. Mayuka Shiino and Ms. Mai Tadaki for technical assistance. This work was supported by a Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (to YK and YF) and research grants from Janssen Pharmaceutical K.K. and the Bristol-Myers Squibb Foundation (to YF). This study was funded by Celgene K.K.

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Authors and Affiliations

  1. Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan

    Yoshiaki Kuroda, Daisuke Koyama, Jiro Kikuchi & Yusuke Furukawa

  2. Department of Hematology, National Hospital Organization Hiroshimanishi Medical Center, 4-1-1 Kuba, Otake, Hiroshima, 739-0696, Japan

    Yoshiaki Kuroda

  3. Department of Pathology, School of Medicine, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa, Iwate, 028-3694, Japan

    Akiko Yashima-Abo

  4. Medical Education Center, Saitama Medical University, 38 Morohongo, Saitama, 350-0495, Japan

    Shigehisa Mori

  5. Hematology and Oncology, Department of Internal Medicine, School of Medicine, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa, Iwate, 028-3694, Japan

    Shigeki Ito

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  1. Yoshiaki Kuroda
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Contributions

YK designed and performed experiments, analyzed data, and drafted the manuscript. AY-A, SM, and SI provided clinical materials and reviewed the manuscript. DK and JK performed experiments and reviewed the manuscript. YF designed and supervised the research, and compiled the manuscript.

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Correspondence to Yusuke Furukawa.

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Kuroda, Y., Yashima-Abo, A., Koyama, D. et al. Bone marrow stromal cell-mediated degradation of CD20 leads to primary rituximab resistance in mantle cell lymphoma. Leukemia 35, 1506–1510 (2021). https://doi.org/10.1038/s41375-020-01035-x

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