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Myeloid cell-based delivery of IFN-γ reprograms leukemia microenvironment and induces anti-tumoral immune responses

ABSTRACT: Myeloid cell-based delivery of IFN-γ reprograms leukemia microenvironment and induces anti-tumoral immune responses

PROVIDER: PRJNA741522 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14916477_1.fastq.gz	Fastqsanger.gz
	SRR14916477_2.fastq.gz	Fastqsanger.gz
	SRR14916478_1.fastq.gz	Fastqsanger.gz
	SRR14916478_2.fastq.gz	Fastqsanger.gz
	SRR14916479_1.fastq.gz	Fastqsanger.gz

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Myeloid cell-based delivery of IFN-γ reprograms leukemia microenvironment and induces anti-tumoral immune responses

Project description:The immunosuppressive microenvironment surrounding tumor cells represents a key cause of treatment failure. Therefore, immunotherapies aimed at reprogramming the immune system have largely spread in the past years. We employed gene transfer into hematopoietic stem and progenitor cells to selectively express anti-tumoral cytokines in tumor-infiltrating monocytes/macrophages. We show that Interferon-γ (IFNγ) reduced tumor progression in mouse models of B-cell acute lymphoblastic leukemia (B-ALL) and colorectal carcinoma (MC38). Its activity was dependent on the capacity of the immune system to respond to IFNγ and drove counter-selection of leukemia cells expressing surrogate antigens. Gene-based IFNγ delivery induced antigen presentation in the myeloid compartment and on leukemia cells, leading to a wave of T cell recruitment and activation, with enhanced clonal expansion of cytotoxic CD8+ T lymphocytes. The activity of IFNγ was further enhanced by either co-delivery of tumor necrosis factor α (TNFα) or by drugs blocking immunosuppressive escape pathways, with the potential to obtain durable responses.

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Project description:The immunosuppressive microenvironment surrounding tumor cells represents a key cause of treatment failure. Therefore, immunotherapies aimed at reprogramming the immune system have largely spread in the past years. We employed gene transfer into hematopoietic stem and progenitor cells to selectively express anti-tumoral cytokines in tumor-infiltrating monocytes/macrophages. We show that interferon-γ (IFN-γ) reduced tumor progression in mouse models of B-cell acute lymphoblastic leukemia (B-ALL) and colorectal carcinoma (MC38). Its activity depended on the immune system's capacity to respond to IFN-γ and drove the counter-selection of leukemia cells expressing surrogate antigens. Gene-based IFN-γ delivery induced antigen presentation in the myeloid compartment and on leukemia cells, leading to a wave of T cell recruitment and activation, with enhanced clonal expansion of cytotoxic CD8+ T lymphocytes. The activity of IFN-γ was further enhanced by either co-delivery of tumor necrosis factor-α (TNF-α) or by drugs blocking immunosuppressive escape pathways, with the potential to obtain durable responses.

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Project description:A greater understanding of hematopoietic stem cell (HSC) regulation is required for dissecting protective versus detrimental immunity to pathogens that cause chronic infections such as Mycobacterium tuberculosis (Mtb). We have shown that systemic administration of BCG or b-glucan reprograms HSCs in the BM via a type II interferon (IFN-II) or IL1 response, respectively, that confers protective trained immunity against Mtb. Yet, whether BCG/β-Glucan is unique in its ability to induce this protection remains unknown. Herein, we demonstrate that unlike BCG or b-glucan, Mtb reprograms HSCs via IFN-I response that suppresses myelopoiesis and impairs protective trained immunity to Mtb. Mechanistically, IFN-I response dysregulates iron metabolism, depolarizes mitochondrial membrane potential, and induces cell death in myeloid progenitors. Finally, activation of IFN-I/iron axis in myeloid progenitors generates a detrimental trained immunity to Mtb infection. These results identify an unanticipated immune evasion strategy of Mtb in the bone marrow that controls the magnitude and anti-microbial capacity of innate immunity to infection

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M. tuberculosis reprograms HSCs to limit myelopoiesis and impair trained immunity via a type I IFN/iron axis [EG_SERIES_3]

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M. tuberculosis reprograms HSCs to limit myelopoiesis and impair trained immunity via a type I IFN/iron axis [Bulk_SERIES_1]

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