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Autoimmunity checkpoints as therapeutic targets in B cell malignancies

Abstract

Targeted therapy of cancer typically focuses on inhibitors (for example, tyrosine kinase inhibitors) that suppress oncogenic signalling below a minimum threshold required for survival and proliferation of cancer cells. B cell acute lymphoblastic leukaemia and B cell lymphomas originate from various stages of development of B cells, which, unlike other cell types, are under intense selective pressure. The vast majority of newly generated B cells are autoreactive and die by negative selection at autoimmunity checkpoints (AICs). Owing to ubiquitous encounters with self-antigen, autoreactive B cells are eliminated by the overwhelming signalling strength of their autoreactive B cell receptor (BCR). A series of recent findings suggests that, despite malignant transformation, AICs are fully functional in B cell malignancies. This Opinion article proposes targeted engagement of AICs as a previously unrecognized therapeutic opportunity to overcome drug resistance in B cell malignancies.

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Figure 1: Pathways of positive and negative selection during early B cell development.
Figure 2: Regulation of B cell receptor signalling strength and its oncogenic mimics in clonal selection of normal and malignant B cell populations.
Figure 3: Concept of transient autoimmunity checkpoint activation to overcome drug resistance in B cell malignancies.

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Acknowledgements

The author thanks Z. Chen, S. Shojaee, S. Swaminathan, G. Xiao, L. N. Chan, T. Sadras and other current and former members of his laboratory as well as T. G. Graeber (Los Angeles, California, USA), A. Weiss and C. A. Lowell (San Francisco, California, USA), H. Jumaa (Ulm, Germany), A. Melnick (New York, New York, USA), N. Bottini (La Jolla, California, USA), J. U. Jung (Los Angeles, California, USA) and L. M. Staudt (Bethesda, Maryland, USA) for critical discussions and encouragement. M.M. is a Howard Hughes Medical Institute Faculty Scholar, a Scholar of the Leukemia and Lymphoma Society and a Senior Investigator of the Wellcome Trust and is supported by a National Cancer Institute (NCI) Outstanding Investigator Award (R35CA197628).

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M.M. developed the autoimmunity checkpoint concept, researched the data and wrote the manuscript.

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Correspondence to Markus Müschen.

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Research in M.M.'s laboratory to elucidate the mechanisms of autoimmunity checkpoints concept activation in B cell malignancies and feasibility of drug-targeting is currently supported by research funding from AbbVie Inc. and Pfizer.

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Müschen, M. Autoimmunity checkpoints as therapeutic targets in B cell malignancies. Nat Rev Cancer 18, 103–116 (2018). https://doi.org/10.1038/nrc.2017.111

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