Inhibition of CtBP complex and FBXO11 enhances MHC class II expression and antitumor immune response

Acute myeloid leukemia (AML) is a clonal malignant proliferative disease of the hematopoietic system’s myeloid primitive cells that is highly heterogeneous, usually incurable with chemotherapy, has a poor prognosis, and is prone to relapse. Allogeneic stem cell transplantation (AlloSCT) is the only treatment option for patients with a poor prognosis, but the risk of relapse persists after transplantation.

Acute myeloid leukemia relapse after allogeneic stem cell transplantation has been linked to a decrease in major histocompatibility complex (MHC) class II expression in leukemic cells, implying a prognostic role for the MHC class II in anti-cancer immunity in tumor cells. However, the molecular mechanisms underlying the regulation of MHC class II during immune escape promotion remain unknown.

Recently, Mark A. Dawson’s group from the Peter MacCallum Cancer Centre at the University of Melbourne published an article in Cancer Cell titled “Inhibition of the CtBP complex and FBXO11 enhances MHC class II expression and anti-cancer immune responses”.

In this study, a CRISPR/Cas9 screen revealed that the C-terminal binding protein (CtBP) complex represses the transcription of MHC class II genes and related pathways, and that CIITA is the major transcription factor regulating MHC class II expression, and FBXO11 in the E3 ubiquitin ligase complex mediates the degradation of CIITA. In acute myeloid leukemia cell lines, upregulation of MHC class II expression can be selectively induced by targeting the above-mentioned repressive mechanisms. This study provides a theoretical basis for reducing acute myeloid leukemia relapse after alloSCT and improving immunotherapy outcomes in acute myeloid leukemia patients.

To identify negative regulators of MHC class II expression, investigators performed a genome-wide CRISPR-Cas9 screening in acute myeloma leukemia cell lines (MOLM13 and OCI-AML3) and identified two potential regulatory genes, FBXO11, and the zinc finger transcription factor RREB1. Knocking out RREB1 and FBXO11 induced MHC class II expression on the surface of these cell lines. Furthermore, it was discovered that FBXO11 interacts directly with CIITA and that the presence of FBXO11 and CIITA ubiquitination are linked. Further screening for epistatic regulators and transcription factors led to additional screening for CtBP complex components, and knockdown or inhibition of these CtBP complex members increased MHC class II expression similarly.

By studying in a mouse model of acute myeloid leukemia that does not express MHC class II, it was found that deletion of Fbxo11 and Rreb1 did not increase the level of surface MHC class II, implying that the inhibitory mechanisms regulating MHC class II expression differ in humans and mice. Therefore, the researchers re-performed CRISPR screening experiments in mice to identify potential regulators of MHC class II, Rcor1 and Zfp217, in murine acute myeloid leukemia cells. Research data suggest that human and murine leukemia cells can process and present antigens through a functional MHC class II pathway, leading to antigen-dependent activation of CD4+ T cells that exert an anti-tumor immune effect.

In summary, this study identified the underlying mechanism of MHC class II suppression in acute myeloid leukemia — the CtBP complex is the primary regulator of MHC class II gene expression, while FBXO11 acts indirectly through post-translational control of CIITA. The role of MHC class II in the adaptive immune response was elucidated, demonstrating that leukemic cells expressing MHC class II activate CD4+ T cells in an antigen-dependent manner, stimulate CD4+ T cell-mediated cytotoxicity, and enhance the function of CD8+ effector T cells. It was also discovered that CtBP complex targeting had no effect on MHC class I expression levels, whereas PRC2 inhibition had no effect on MHC class II expression levels, implying that MHC class I and MHC class II expression are regulated by independent chromatin repression complexes.