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

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

Author(s): Chan, KL; Gomez, J; Cardinez, C; Kumari, N; Sparbier, CE; Lam, EYN; Yeung, MM; Garciaz, S; Kuzich, JA; Ong, DM; Brown, FC; Chan, YC; Vassiliadis, D; Wainwright, EN; Motazedian, A; Gillespie, A; Fennell, KA; Lai, J; House, IG; MacPherson, L; Ang, CS; Dawson, SJ; Beavis, PA; Wei, AH; Burr, ML; Dawson, MA;
Details: Publication Year 2022-10-10,Volume 40,Issue #10,Page 1190-1206.e9
Journal Title: Cancer Cell
Publication Type: Research article
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: Alcohol Oxidoreductases; DNA-Binding Proteins; *F-Box Proteins/genetics; HLA Antigens/genetics; Histocompatibility Antigens Class II/genetics/metabolism; Humans; *Leukemia, Myeloid, Acute/genetics/therapy; Lymphocyte Activation; Protein-Arginine N-Methyltransferases/metabolism; Recurrence; Transcription Factors/metabolism; Ubiquitin-Protein Ligases/genetics/metabolism; CtBP; Fbxo11; MHC class II; acute myeloid leukemia; bone marrow transplantation; cancer epigenetics; gene regulation; melanoma; tumor immunology
Department(s): Laboratory Research; Clinical Haematology; Medical Oncology
PubMed ID: 36179686
Publisher's Version: https://doi.org/10.1016/j.ccell.2022.09.007
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-10-15 10:33:27

Last Modified: 2024-10-15 10:33:48