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

• Published in: Cancer cell Vol. 40; no. 10; pp. 1190 - 1206.e9
• Main Authors: Chan, Kah Lok, Gomez, Juliana, Cardinez, Chelisa, Kumari, Nishi, Sparbier, Christina E., Lam, Enid Y.N., Yeung, Miriam M., Garciaz, Sylvain, Kuzich, James A., Ong, Doen Ming, Brown, Fiona C., Chan, Yih-Chih, Vassiliadis, Dane, Wainwright, Elanor N., Motazedian, Ali, Gillespie, Andrea, Fennell, Katie A., Lai, Junyun, House, Imran G., Macpherson, Laura, Ang, Ching-Seng, Dawson, Sarah-Jane, Beavis, Paul A., Wei, Andrew H., Burr, Marian L., Dawson, Mark A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.10.2022
• Subjects: acute myeloid leukemia; Alcohol Oxidoreductases; bone marrow transplantation; cancer epigenetics; CtBP; DNA-Binding Proteins; F-Box Proteins - genetics; FBXO11; gene regulation; Histocompatibility Antigens Class II - genetics; Histocompatibility Antigens Class II - metabolism; HLA Antigens - genetics; Humans; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - therapy; Lymphocyte Activation; melanoma; MHC class II; Protein-Arginine N-Methyltransferases - metabolism; Recurrence; Transcription Factors - metabolism; tumor immunology; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; tumor immunology; acute myeloid leukemia; gene regulation; melanoma; cancer epigenetics; MHC class II; FBXO11; bone marrow transplantation; CtBP
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccell.2022.09.007

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. [Display omitted] •The CtBP complex transcriptionally represses MHC class II pathway genes in AML•FBXO11 restricts MHC class II expression by targeting CIITA for degradation•Restoring MHC class II expression on leukemic blasts stimulates CD4+ T cell responses•Inducing tumor cell MHC class II may enhance alloSCT and immunotherapy outcomes Chan et al. identify specific transcriptional and post-translational regulators of MHC class II in acute myeloid leukemia and melanoma cells. Targeting these repressive mechanisms efficiently restores tumor cell MHC class II expression and stimulates potent anti-cancer immune responses, representing a promising therapeutic strategy to improve allogeneic stem cell transplantation and immunotherapy outcomes.