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

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

  • Cancer Cell. 2022 Oct 10;40(10):1190-1206.e9. doi: 10.1016/j.ccell.2022.09.007.
Kah Lok Chan 1,  Juliana Gomez 2,  Chelisa Cardinez 3,  Nishi Kumari 4,  Christina E Sparbier 5,  Enid Y N Lam 5,  Miriam M Yeung 4,  Sylvain Garciaz 6,  James A Kuzich 5,  Doen Ming Ong 7,  Fiona C Brown 8,  Yih-Chih Chan 5,  Dane Vassiliadis 5,  Elanor N Wainwright 5,  Ali Motazedian 5,  Andrea Gillespie 4,  Katie A Fennell 5,  Junyun Lai 5,  Imran G House 5,  Laura Macpherson 5,  Ching-Seng Ang 9,  Sarah-Jane Dawson 10,  Paul A Beavis 5,  Andrew H Wei 7,  Marian L Burr 11,  Mark A Dawson 12
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Division of Genome Science and Cancer, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2601, Australia.
  • 4 Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
  • 5 Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia.
  • 6 Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Aix-Marseille University, INSERM U1068, CNRS, Institut Paoli-Calmettes, 13009 Marseille, France.
  • 7 Australian Centre for Blood Diseases, Monash University, Melbourne, VIC 3004, Australia; Department of Haematology, The Alfred Hospital, Melbourne, VIC 3004, Australia.
  • 8 Australian Centre for Blood Diseases, Monash University, Melbourne, VIC 3004, Australia.
  • 9 Melbourne Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC 3010, Australia.
  • 10 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.
  • 11 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.
  • 12 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.
PMID: 36179686 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 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.

Keywords

CtBP; FBXO11; MHC class II; acute myeloid leukemia; bone marrow transplantation; cancer epigenetics; gene regulation; melanoma; tumor immunology.

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