Project description:Persistent therapy-resistant leukemia 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 demonstrated 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 identified AML/LPC-associated HLA-presented antigens including 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.
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.
Project description:To identify potential T-cell targets for Triple-Negative Breast Cancer (TNBC) vaccination, we examined the effect of the pro-inflammatory cytokine interferon-γ (IFNγ) on the transcriptome, proteome and immunopeptidome of the TNBC cell line MDA-MB-231. Using high resolution mass spectrometry, we identified a total of 84,131 peptides from 9,647 source proteins presented by human leukocyte antigen (HLA)-I and HLA-II alleles. Treatment with IFNγ resulted in a remarkable remoulding of the immunopeptidome, with only a 34% overlap between untreated and treated cells across the HLA-I immunopeptidome, and expression of HLA-II only on treated cells. IFNγ increased the overall number, diversity and abundance of the immunopeptidome, as well as the proportion of coverage of source antigens. The suite of peptides displayed under conditions of IFNγ treatment included many known tumour associated antigens, with the HLA-II repertoire sampling 265 breast cancer associated antigens absent from those sampled by HLA-I. Quantitative analysis of the transcriptome (10,248 transcripts) and proteome (6783 proteins) of these cells revealed 229 proteins and transcripts were commonly differentially expressed, most of which involved in downstream targets of IFNγ signalling including components of the antigen processing machinery such as tapasin and HLA. However, these changes in protein expression did not explain the dramatic modulation of the immunopeptidome following IFNγ treatment. These results demonstrate the high degree of plasticity in the immunopeptidome TNBC cells following cytokine stimulation and provide evidence that under pro-inflammatory conditions a greater variety of HLA-I and HLA-II vaccine targets are unveiled to the immune system. This has important implications for the development of personalised cancer vaccination strategies.
Project description:Microarrays transcriptomic data analyses from acute myeloid leukemia cell line OCI-AML2 and primary acute myeloid leukemia cells treated with actinomycin D.
Project description:Acute myeloid leukemia cell lines were treated with the hypomethylating agent decitabine and interferon gamma to investigate if these treatments induce HLA II gene expression. Cells carrying either control or CIITA-targeting sgRNAs were used to test the dependence of the HLA II induction on CIITA.
Project description:Acute myeloid leukemia cell lines were treated with the hypomethylating agent decitabine and interferon gamma to investigate if these treatments induce HLA II gene expression. Cells carrying either control or CIITA-targeting sgRNAs were used to tet
Project description:The goal of this study was to determine the effects of gene deletions and duplications on acute myeloid leukemia cells immunogenicity. The Clones were derived from the C1498 AML cell line. Lymphocytes were isolated from the C57BL/6 mouse strain. Genome profiling of mouse single cell clones originating from an acute myeloid leukemia cell line compared to control T lymphocytes from the same murine strain.
Project description:The goal of this study was to determine the effects of gene deletions and duplications on acute myeloid leukemia cells immunogenicity. The Clones were derived from the C1498 AML cell line. Lymphocytes were isolated from the C57BL/6 mouse strain. Genome profiling of mouse single cell clones originating from an acute myeloid leukemia cell line compared to control T lymphocytes from the same murine strain.
Project description:Transcriptome profiling of Acute Myeloid Leukemia samples. This dataset includes patients with diagnosis of de novo or secondary AML who experienced non-HLA loss disease relapse after allo-HCT, and for whom paired pre- and post-transplant viable leukemic samples were available.