Inhibition of the CtBP complex and FBXO11 enhances MHC class II expression and anti-cancer immune responses

KL Chan; J Gomez; C Cardinez; N Kumari; CE Sparbier; EYN Lam; MM Yeung; S Garciaz; JA Kuzich; DM Ong; FC Brown; YC Chan; D Vassiliadis; EN Wainwright; A Motazedian; A Gillespie; KA Fennell; J Lai; IG House; L Macpherson; CS Ang; SJ Dawson; PA Beavis; AH Wei; ML Burr; MA Dawson

Journal article

Inhibition of the CtBP complex and FBXO11 enhances MHC class II expression and anti-cancer immune responses

KL Chan, J Gomez, C Cardinez, N Kumari, CE Sparbier, EYN Lam, MM Yeung, S Garciaz, JA Kuzich, DM Ong, FC Brown, YC Chan, D Vassiliadis, EN Wainwright, A Motazedian, A Gillespie, KA Fennell, J Lai, IG House, L Macpherson Show all

Cancer Cell | Published : 2022

DOI: 10.1016/j.ccell.2022.09.007

Abstract

There is increasing recognition of the prognostic significance of tumor cell major histocompatibility complex (MHC) class II expression in anti-cancer immunity. Relapse of acute myeloid leukemia (AML) following allogeneic stem cell transplantation (alloSCT) has recently been linked to MHC class II silencing in leukemic blasts; however, the regulation of MHC class II expression remains incompletely understood. Utilizing unbiased CRISPR-Cas9 screens, we identify that the C-terminal binding protein (CtBP) complex transcriptionally represses MHC class II pathway genes, while the E3 ubiquitin ligase complex component FBXO11 mediates degradation of CIITA, the principal transcription factor regulat..

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University of Melbourne Researchers

Kah Lok Chan Author

Enid Lam Author

Chih Chan Author

Dane Vassiliadis Author

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Funding Acknowledgements

We thank the Flow Cytometry facility and Molecular Genomics Core at the Peter MacCallum Cancer Center, as well as S. Jackson, J. Schreuders, R. Walker, K. Warren, B. Blyth, H. Beetham, and K. Simpson for their technical contributions to this project. We thank the following funders for fellowship, scholarship, and grant support: NHMRC Postgraduate Scholarship and HSANZ New Investigator Scholarship (K.L.C.); Snow Fellowship supported by the Snow Medical Research Foundation (M.L.B.); NHMRC Investigator Grant 1196598 and Cancer Research UK Clinician Scientist Fellowship C53779/A20097 (M.L.B.); Cancer Council Victoria Sir Edward Dunlop Research Fellowship, NHMRC Investigator Grant 1196749, and Howard Hughes Medical Institute International Research Scholarship 55008729 (M.A.D.); Peter MacCallum Postgraduate Scholarship (C.E.S.); VCA Early Career Research Fellowship (I.G.H.); VCA Mid-Career Research Fellowship (E.Y.N.L. and P.A.B.); US Cancer Research Institute Irvington Postdoctoral Fellowship (J.L.); Nuovo-Soldati Foundation for Cancer Research and Fondation de France (S.G.); NHMRC Investigator Grant 1176175 (F.C.B.); Leukemia and Lymphoma Society, US, Specialized Center of Research grant 7015-18 and Medical Research Future Fund Fellowship 1141460 (A.H.W.); CSL Centenary Fellowship and NHMRC Investigator Grant 1196755 (S.-J.D.); and NHMRC grants 1164054/2010275 (M.L.B.), 1085015/1106444 (M.A.D.), and 1128984 (M.A.D. and S.-J.D.). Schematics of experimental workflows were created with BioRender.com.