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Inhibition of the CtBP complex and FBXO11 enhances MHC class II expression and anti-cancer immune responses [CUT&TAG]

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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE189771 | GEO | 2022/10/02

REPOSITORIES: GEO

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

Project description: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.

2022-10-02 | GSE189767 | GEO

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

2022-10-02 | GSE189772 | GEO

Inhibition of the CtBP complex and FBXO11 enhances MHC class II expression and anti-cancer immune responses [Whole-genome CRISPRscreen]

2022-10-02 | GSE189769 | GEO

Single-cell analysis reveals altered tumor microenvironments of relapse- and remission-associated pediatric acute myeloid leukemia

Project description:Pediatric acute myeloid leukemia (AML) bone marrow (BM) samples from diagnosis (Dx), end of induction (EOI), and relapse timepoints were analyzed by single-cell RNA sequencing (scRNA-seq). Analysis of matched Dx, EOI scRNA-seq datasets and TARGET AML RNA-seq datasets revealed a novel AML blasts-associated 7-gene signature (CLEC11A, PRAME, AZU1, NREP, ARMH1, C1QBP, TRH) that was validated in two independent datasets. Distinct clusters of relapse- and continuous complete remission (CCR)-associated AML-blasts were observed at Dx, with differential expression of genes associated with survival. At Dx, relapse-associated samples had more exhausted T cells while CCR-associated samples had more inflammatory M1 macrophages. Post-therapy EOI residual blasts overexpressed fatty acid oxidation, tumor growth, and stemness genes. Also, a post-therapy T-cells cluster present in relapse-associated samples exhibited downregulation of MHC Class I and T-cell regulatory genes. Altogether, this study deeply characterizes pediatric AML relapse- and CCR-associated samples to provide novel insights into BM microenvironment landscape.

2023-09-05 | GSE235923 | GEO

Immune Escape after Allogeneic Hematopoietic Cell Transplantation in Pediatric Patients with Acute Myeloid Leukemia

Project description:Although allogeneic hematopoietic cell transplantation (allo-HCT) is curative for high-risk pediatric acute myeloid leukemia (AML), disease relapse remains the primary cause of post-transplant mortality. To identify pressures imposed by allo-HCT on AML cells that escape the graft-versus-leukemia effect, we evaluated immune signatures in bone marrow samples from four pediatric patients using a multimodal single-cell approach. Downregulation of MHC class II (MHC-II) expression observed at post-transplant relapse was most profound in progenitor-like blasts and was accompanied by correlative changes in transcriptional regulation. Dysfunction of activated NK cells and CD8+ T cell subsets at the time of relapse was evidenced by the loss of IFN-γ response, TNF-a signaling via NF-kB, and IL-2/STAT5 signaling. Clonotype analysis of post-transplant relapse samples revealed expansion of dysfunctional T cells and enrichment of T regulatory and T helper cells. Using novel computational methods, our results illustrate a diverse immune-related transcriptional signature in post-transplantation relapses not previously reported in pediatric AML.

2023-06-26 | GSE207104 | GEO

Blast cells surviving acute myeloid leukemia induction therapy are in cycle with a signature of FOXM1 activity

Project description:Disease relapse remains common following treatment of acute myeloid leukemia (AML) and is due to chemoresistance of leukemia cells with disease repopulating potential. To date, attempts to define the characteristics of in vivo resistant blasts have focused on comparisons between leukemic cells at presentation and relapse. However, further treatment responses are often seen following relapse, suggesting that most blasts remain chemosensitive. Here we characterize in vivo chemoresistant blasts by studying the transcriptional and genetic features of blasts from before and after induction chemotherapy using paired samples from 6 patients with primary refractory AML.

2021-10-04 | GSE162542 | GEO

CKS1-dependent proteostatic regulation has dual roles in combating acute myeloid leukemia whilst protecting normal hematopoiesis

Project description:Acute myeloid leukemia (AML) is an aggressive hematological disorder comprised of a hierarchy of quiescent leukemic stem cells and fast proliferating blasts with limited self-renewal ability. Significant plasticity in the AML epigenome and metabolome results in a high rate of drug resistance and relapse, with extremely low 2-year survival rates in the poorest cytogenetic risk patients. The current backbone of clinical induction chemotherapy reduces total disease burden, but does not deplete leukemic stem cells which reconstitute the disease in vivo, and also suffers from severe toxicity of healthy hematopoietic cells. Whilst much work has been done to identify epigenetic vulnerabilities in AML, little is known about protein dynamics, and here we explored the therapeutic inhibition of highly specific CKS1-dependent protein degradation. We report a dual role for CKS1-depdent protein degradation in specifically targeting AML, whilst protecting normal hematopoietic cells from chemotherapeutic toxicity.

2022-07-20 | PXD022754 | Pride

Immune surveillance of acute myeloid leukemia is mediated by HLA-presented antigens on leukemia progenitor cells

Project description:Persistent therapy-resistant leukemic progenitor cells (LPC) are a main cause of disease relapse and recurrence in acute myeloid leukemia (AML). Specific LPC-targeting therapies may thus improve treatment outcome of AML patients. We demonstrate that LPCs present human leukocyte antigen (HLA)-restricted cancer antigens that induce T cell responses allowing for immune surveillance of AML. Using a mass spectrometry-based immunopeptidomics approach we characterized the antigenic landscape of patient LPCs and identify AML/LPC-associated HLA-presented antigens as well as mutation-derived and cryptic neoepitopes as prime targets for development of T cell-based immunotherapeutic approaches. We observed frequent spontaneous memory T cells targeting these AML/LPC-associated antigens in AML patients and showed that antigen-specific T cell recognition and HLA class II immunopeptidome diversity impacts clinical outcome. Our results pave the way for implementation of AML/LPC-associated antigens for T cell-based immunotherapeutic approaches to specifically target and eliminate residual LPCs in AML patients.

2023-08-23 | PXD038691 | Pride

RNA-Seq identifies alternative splicing of CRBN induced by ILF3 KO

Project description:We present a first-in-class GSPT1-selective CELMoD, CC-90009, which is currently in a phase 1 clinical trial for the treatment of relapsed or refractory (R/R) AML (CC-90009-AML-001; NCT02848001). Biochemical, structural and molecular characterization supports that CC-90009 coopts the CUL4-DDB1-CRBN-RBX1 (CRL4-CRBN) E3 ubiquitin ligase complex to selectively target GSPT1 for ubiquitination and proteasomal degradation, culminating in rapid induction of apoptosis and growth inhibition in AML cell lines and patient leukemic blasts. Knockout of ILF2/ILF3 decreased the production of full-length CRBN transcript via modulating CRBN mRNA alternative splicing, leading to significant downregulation of cereblon expression and hence diminished response to CC-90009.

2021-02-05 | GSE154257 | GEO

Type I interferon signaling in malignant blasts contributes to treatment efficacy in AML patients

Project description:While type I interferon (IFN) is best known for its key role against viral infection, accumulating preclinical and clinical data indicate that robust type I IFN production in the tumor microenvironment promotes cancer immunosurveillance and contributes to the efficacy of various antineoplastic agents, notably immunogenic cell death inducers. Here, we report that malignant blasts from patients with acute myeloid leukemia (AML) release type I IFN via a Toll-like receptor (TLR3)-dependent mechanism that is not influenced by treatment. While in these patients the ability of type I IFN to stimulate anticancer immune responses was abolished by immunosuppressive mechanisms driven by malignant blasts, type I IFN turned out to exert direct cytostatic, cytotoxic and chemosensitizing activity in primary AML blasts, leukemic stem cells from AML patients and AML xenograft models. Finally, a genetic signature of type I IFN signaling has independent prognostic value on relapse-free survival and overall survival in cohort of 132 AML patients. These findings delineate a clinically relevant, therapeutically actionable and prognostically informative mechanism through which type I IFN mediates beneficial effects in patients with AML.

2023-03-24 | GSE225138 | GEO

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