Flt3L therapy induces a Treg‐promoting cDC1 state in triple‐negative breast cancer
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ABSTRACT:
PROVIDER: PRJNA936137 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23509320_1.fastq.gz | Fastqsanger.gz | |||
| SRR23509320_2.fastq.gz | Fastqsanger.gz | |||
| SRR23509321_1.fastq.gz | Fastqsanger.gz | |||
| SRR23509321_2.fastq.gz | Fastqsanger.gz | |||
| SRR23509322_1.fastq.gz | Fastqsanger.gz |
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Project description:Conventional dendritic cells (cDCs) are at the forefront of activating the immune system to mount an anti‐tumor immune response. Flt3L is a cytokine required for DC development that can increase DC abundance in the tumor when administered therapeutically. However, the impact of Flt3L on the phenotype of distinct cDC subsets in the tumor microenvironment is still largely undetermined. Here, using multi‐omic single‐cell analysis, we show that Flt3L therapy increases all cDC subsets in orthotopic E0771 triple‐negative breast cancer, but this did not result in a reduction of tumor growth. Interestingly, a CD81+migcDC1 population, likely developing from cDC1, was induced upon Flt3L treatment. This subset is characterized by the expression of both canonical cDC1 markers as well as migratory cDC activation and regulatory markers and displayed a higher Treg‐inducing potential compared to other migcDCs. To shift the cDC phenotype towards a T‐cell stimulatory phenotype, CD40 agonist therapy was administered in combination with Flt3L. However, while αCD40 reduced tumor growth, Flt3L failed to improve the therapeutic response to αCD40 therapy. Interestingly, Flt3L+αCD40 combination therapy increased the abundance of Treg promoting CD81+migcDC1. Nonetheless, while Treg‐depletion and αCD40 therapy were synergistic, the addition of Flt3L to this combination did not result in any added benefit. Overall, these results indicate that merely increasing cDCs in the tumor by Flt3L treatment cannot improve anti‐tumor responses and therefore might not be beneficial for the treatment of triple‐negative breast cancer, though could still be of use to increase cDC numbers for autologous DC‐therapy.
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Project description:Flt3 ligand (Flt3L) promotes an increased generation of type 1 conventional dendritic cells (cDC1s), resulting in enhanced immunity against infections and cancer. Here, we employ cellular barcoding to understand how Flt3L regulates single haematopoietic stem and progenitor cell (HSPC) fate. Our results demonstrate that although Flt3L stimulation can recruit some additional cDC1-generating HSPCs, the major contributing factor to higher cDC1 numbers is through enhanced clonal expansion. This selective cDC1 expansion occurs primarily via multi-/oligo-potent clones, without compromising their clonal output to other lineages. We then develop Divi-Seq to simultaneously profile division history, surface phenotype and the transcriptional state of single HSPCs during the early phase of the response. We discover that Flt3L-responsive HSPCs maintain a proliferative ‘early progenitor’-like state, which leads to a selective emergence of CD11c+cKit+ transitional precursors with high cellular output to cDC1s. These findings inform the mechanistic action of Flt3L in natural immunity and immunotherapy.
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Project description:Dendritic cells (DCs) are specialized myeloid cells with the ability to uptake, process, and present antigens to T lymphocytes. They also generate cytokine and chemokine gradients that regulate immune cell trafficking, activation, and function. Monocyte-derived DCs (moDCs) pulsed with tumor antigens have been used as a platform for therapeutic vaccination in cancer. However, in spite of significant development and testing, antigen-loaded moDCs have delivered mixed clinical results. Here we present a DC therapy that uses a population of mouse or human DC progenitors (DCPs) engineered to produce two immunostimulatory cytokines, IL-12 and FLT3L. In the absence of antigen loading, cytokine-armored DCPs efficiently differentiated into conventional type I DCs (cDC1) and inhibited tumor growth in melanoma and autochthonous liver cancer models. Tumor response to DCP therapy involved synergy between IL-12 and FLT3L and was associated with early NK cell activation and massive effector T cell infiltration, robust M1-like macrophage programming, and ischemic tumor necrosis. Mechanistically, anti-tumor immunity was dependent on endogenous cDC1 expansion and interferon-γ (IFNγ) production and signaling, but did not require CD8+ T cell cytotoxicity. In one application, cytokine-armored DCPs synergized with antigen-specific CAR-T cells to eradicate intracranial gliomas in mice.
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Project description:Dendritic cells (DCs) are specialized myeloid cells with the ability to uptake, process, and present antigens to T lymphocytes. They also generate cytokine and chemokine gradients that regulate immune cell trafficking, activation, and function. Monocyte-derived DCs (moDCs) pulsed with tumor antigens have been used as a platform for therapeutic vaccination in cancer. However, in spite of significant development and testing, antigen-loaded moDCs have delivered mixed clinical results. Here we present a DC therapy that uses a population of mouse or human DC progenitors (DCPs) engineered to produce two immunostimulatory cytokines, IL-12 and FLT3L. In the absence of antigen loading, cytokine-armored DCPs efficiently differentiated into conventional type I DCs (cDC1) and inhibited tumor growth in melanoma and autochthonous liver cancer models. Tumor response to DCP therapy involved synergy between IL-12 and FLT3L and was associated with early NK cell activation and massive effector T cell infiltration, robust M1-like macrophage programming, and ischemic tumor necrosis. Mechanistically, anti-tumor immunity was dependent on endogenous cDC1 expansion and interferon-γ (IFNγ) production and signaling, but did not require CD8+ T cell cytotoxicity. In one application, cytokine-armored DCPs synergized with antigen-specific CAR-T cells to eradicate intracranial gliomas in mice.
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Project description:Conventional dendritic cells (cDCs) are at the forefront of activating the immune system to mount an anti-tumor immune response. Flt3L is a cytokine required for DC development that can increase DC abundance in the tumor when administered therapeutically. However, the impact of Flt3L on the phenotype of distinct cDC subsets in the tumor microenvironment is still largely undetermined. Here, using multi-omic single-cell analysis, we show that Flt3L therapy increases all cDC subsets in orthotopic E0771 and TS/A breast cancer and LLC lung cancer models, but this did not result in a reduction of tumor growth in any of the models. Interestingly, a CD81+migcDC1 population, likely developing from cDC1, was induced upon Flt3L treatment in E0771 tumors as well as in TS/A breast and LLC lung tumors. This CD81+migcDC1 subset is characterized by the expression of both canonical cDC1 markers as well as migratory cDC activation and regulatory markers and displayed a Treg-inducing potential. To shift the cDC phenotype towards a T-cell stimulatory phenotype, CD40 agonist therapy was administered to E0771 tumor-bearing mice in combination with Flt3L. However, while αCD40 reduced tumor growth, Flt3L failed to improve the therapeutic response to αCD40 therapy. Interestingly, Flt3L+αCD40 combination therapy increased the abundance of Treg-promoting CD81+migcDC1. Nonetheless, while Treg-depletion and αCD40 therapy were synergistic, the addition of Flt3L to this combination did not result in any added benefit. Overall, these results indicate that merely increasing cDCs in the tumor by Flt3L treatment cannot improve anti-tumor responses and therefore might not be beneficial for the treatment of cancer, though could still be of use to increase cDC numbers for autologous DC-therapy.
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