KPNA2 promotes osteosarcoma progression by regulating the alternative splicing of DDX3X mediated by YBX1.

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Abstract

[Indexed for MEDLINE] Conflict of interest statement: Competing interests: LC, KJ, YY, YP, XC, QP, WY, ZZ, ZS, and WW report no conflicts of interest. VT BA reports research grants from Polaris, Pfizer, Merck, Tracon Pharma, GlaxoSmithKline; consulting fees from Bayer, Cytokinetics Inc., Deciphera Pharmaceuticals, Daiichi Sankyo, EcoR1, Advenchen, Putnam, Salarius Pharmaceuticals, Boxer Capital LLC, Acuta Capital Partners LLC, Aadi Biosciences, Race Oncology Limited, Hinge Bio, Inc., and Kronos Bio, Inc.; honoraria for educational talks from Iteration Therapeutics, Inc. and Total Health Conference; fees for participation in Data/Safety Advisory Boards for Apexigen, Daiichi Sankyo, Epizyme, Bayer, PTC Therapeutics, Aadi Biosciences, Boehringer Ingelheim, Agenus, Regeneron Pharmaceuticals, Advenchen, and Curtis; and speaking fees from Caris, Janssen, Lilly, Target Oncology, Bionest Partners, and Intellisphere LLC. Ethical approval: The research was carried out in accordance with the principles outlined in the Declaration of Helsinki. The Animal Use and Care Committees at Tongji Medical College, Huazhong University of Science and Technology approved approval for the research (IACUC Number: [2023] 3790). Consent for publication: All subjects signed a written informed consent. 11. Cancer Cell. 2023 Jan 9;41(1):106-123.e10. doi: 10.1016/j.ccell.2022.11.014. Epub 2022 Dec 15. IL-5-producing CD4(+) T cells and eosinophils cooperate to enhance response to immune checkpoint blockade in breast cancer. Blomberg OS(1), Spagnuolo L(2), Garner H(2), Voorwerk L(3), Isaeva OI(4), van Dyk E(5), Bakker N(2), Chalabi M(6), Klaver C(3), Duijst M(3), Kersten K(3), Brüggemann M(3), Pastoors D(2), Hau CS(2), Vrijland K(2), Raeven EAM(2), Kaldenbach D(2), Kos K(1), Afonina IS(7), Kaptein P(8), Hoes L(9), Theelen WSME(10), Baas P(10), Voest EE(9), Beyaert R(7), Thommen DS(8), Wessels LFA(11), de Visser KE(12), Kok M(13). Author information: (1)Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands; Department of Immunology, Leiden University Medical Centre, Leiden, the Netherlands. (2)Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (3)Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (4)Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (5)Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (6)Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Gastrointestinal Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (7)VIB-UGent Center for Inflammation Research, Ghent University, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. (8)Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (9)Oncode Institute, Utrecht, the Netherlands; Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (10)Department of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (11)Oncode Institute, Utrecht, the Netherlands; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (12)Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands; Department of Immunology, Leiden University Medical Centre, Leiden, the Netherlands. Electronic address: k.d.visser@nki.nl. (13)Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Electronic address: m.kok@nki.nl. Comment in Cancer Cell. 2023 Jan 9;41(1):9-11. doi: 10.1016/j.ccell.2022.11.008. Nat Rev Immunol. 2023 Feb;23(2):72. doi: 10.1038/s41577-022-00832-y. Mol Oncol. 2023 Apr;17(4):545-547. doi: 10.1002/1878-0261.13413. Immune checkpoint blockade (ICB) has heralded a new era in cancer therapy. Research into the mechanisms underlying response to ICB has predominantly focused on T cells; however, effective immune responses require tightly regulated crosstalk between innate and adaptive immune cells. Here, we combine unbiased analysis of blood and tumors from metastatic breast cancer patients treated with ICB with mechanistic studies in mouse models of breast cancer. We observe an increase in systemic and intratumoral eosinophils in patients and mice responding to ICB treatment. Mechanistically, ICB increased IL-5 production by CD4+ T cells, stimulating elevated eosinophil production from the bone marrow, leading to systemic eosinophil expansion. Additional induction of IL-33 by ICB-cisplatin combination or recombinant IL-33 promotes intratumoral eosinophil infiltration and eosinophil-dependent CD8+ T cell activation to enhance ICB response. This work demonstrates the critical role of eosinophils in ICB response and provides proof-of-principle for eosinophil engagement to enhance ICB efficacy. Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved. DOI: 10.1016/j.ccell.2022.11.014