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

Autor:	Chan KL; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Haematology, Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Melbourne, VIC 3000, Australia., Gomez J; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Division of Genome Science and Cancer, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2601, Australia., Cardinez C; Division of Genome Science and Cancer, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2601, Australia., Kumari N; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia., Sparbier CE; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia., Lam EYN; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia., Yeung MM; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia., Garciaz S; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Aix-Marseille University, INSERM U1068, CNRS, Institut Paoli-Calmettes, 13009 Marseille, France., Kuzich JA; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia., Ong DM; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC 3004, Australia; Department of Haematology, The Alfred Hospital, Melbourne, VIC 3004, Australia., Brown FC; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC 3004, Australia., Chan YC; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia., Vassiliadis D; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia., Wainwright EN; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia., Motazedian A; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia., Gillespie A; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia., Fennell KA; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia., Lai J; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia., House IG; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia., Macpherson L; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia., Ang CS; Melbourne Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC 3010, Australia., Dawson SJ; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia; Centre for Cancer Research, The University of Melbourne, Parkville, VIC 3000, Australia., Beavis PA; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia., Wei AH; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC 3004, Australia; Department of Haematology, The Alfred Hospital, Melbourne, VIC 3004, Australia., Burr ML; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia; Division of Genome Science and Cancer, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2601, Australia; Department of Anatomical Pathology, ACT Pathology, Canberra Health Services, Canberra, ACT 2606, Australia. Electronic address: marian.burr@anu.edu.au., Dawson MA; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Haematology, Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Melbourne, VIC 3000, Australia; Centre for Cancer Research, The University of Melbourne, Parkville, VIC 3000, Australia. Electronic address: mark.dawson@petermac.org.
Jazyk:	angličtina
Zdroj:	Cancer cell [Cancer Cell] 2022 Oct 10; Vol. 40 (10), pp. 1190-1206.e9. Date of Electronic Publication: 2022 Sep 29.
DOI:	10.1016/j.ccell.2022.09.007
Abstrakt:	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 regulating MHC class II expression. Targeting these repressive mechanisms selectively induces MHC class II upregulation across a range of AML cell lines. Functionally, MHC class II + leukemic blasts stimulate antigen-dependent CD4 + T cell activation and potent anti-tumor immune responses, providing fundamental insights into the graft-versus-leukemia effect. These findings establish the rationale for therapeutic strategies aimed at restoring tumor-specific MHC class II expression to salvage AML relapse post-alloSCT and also potentially to enhance immunotherapy outcomes in non-myeloid malignancies. Competing Interests: Declaration of interests M.A.D. has been a member of advisory boards for GlaxoSmithKline, CTx CRC, Storm Therapeutics, Celgene, and Cambridge Epigenetix. S.-J.D. has been a member of advisory boards for AstraZeneca. The M.A.D. and S.-J.D. laboratories have received research funding from CTx CRC and Pfizer. The S.-J.D. laboratory has received research funding from Genentech. P.A.B. has received research funding from AstraZeneca, Bristol Myers Squibb, and Gilead Sciences. A.H.W. has been a member of advisory boards for Novartis, Janssen, Amgen, Roche, Pfizer, Abbvie, Servier, Gilead, BMS, Macrogenics, and Agios, receives research funding to the Institution from Novartis, Abbvie, Servier, BMS, Astra Zeneca, and Amgen, and serves on speaker’s bureaus for Abbvie, Novartis, and BMS. All other authors declare no competing interests. (Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu