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Combinational targeting CCL7 and Flt3L to promote the expansion and infiltration of cDC1 in tumors enhances T cell activation and anti-PD-1 therapy

ABSTRACT: Combinational targeting CCL7 and Flt3L to promote the expansion and infiltration of cDC1 in tumors enhances T cell activation and anti-PD-1 therapy

PROVIDER: PRJNA934274 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23426406.fastq.gz	Fastqsanger.gz
	SRR23426407.fastq.gz	Fastqsanger.gz
	SRR23426408.fastq.gz	Fastqsanger.gz
	SRR23426409.fastq.gz	Fastqsanger.gz
	SRR23437191.fastq.gz	Fastqsanger.gz

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Combinational targeting CCL7 and Flt3L to promote the expansion and infiltration of cDC1 in tumors enhances T cell activation and anti-PD-1 therapy [CD8 T]

Project description:Immune checkpoint inhibitors (ICIs) represented by anti-PD-1/PD-L1 antibodies have been widely applied for various cancers and the response rate to ICIs is closely associated with the tumor immune microenvironment (TIME). Here, we show that combinational targeting CCL7 and Fms-like tyrosine kinase 3 ligand (Flt3L) increases the infiltration and expansion of conventional type 1 dendritic cells (cDC1s) in tumor sites and enhances the T cell antitumor responses and the efficacy of anti-PD-1 therapy in subcutaneous tumor models and spontaneous KrasG12D non-small cell lung cancer (NSCLC) models. We demonstrate that the fusion protein PD-1Ab7 in which CCL7 is fused with the single chain fragment variable region of anti-PD-1 antibody (PD-1Ab) exhibits superior antitumor activities compared to PD-1Ab. Mechanistically, PD-1Ab7 promotes antitumor immunity by increasing the infiltration of cDC1s and the activation of T cells, which is severely compromised by depletion of Zbtb46+ cDCs or inhibition of the CCL7 receptor CCR2. Furthermore, complementation of Flt3L sensitizes the ICI-resistant tumors to PD-1Ab7 and synergizes with PD-1Ab7 to inhibit tumor progression. These findings highlight the essential roles of PD-1Ab-based chemokine fusion strategy in targeting cDC1s and T cells for cancer prevention and provide therapeutic lead molecules for antitumor immunotherapy.

2023-02-18 | GSE225163 | GEO

Combinational targeting CCL7 and Flt3L to promote the expansion and infiltration of cDC1 in tumors enhances T cell activation and anti-PD-1 therapy [Dendritic Cell]

2023-02-18 | GSE225126 | GEO

Combinational targeting CCL7 and Flt3L to promote the expansion and infiltration of cDC1 in tumors enhances T cell activation and anti-PD-1 therapy [Dendritic Cell]

Project description:Combinational targeting CCL7 and Flt3L to promote the expansion and infiltration of cDC1 in tumors enhances T cell activation and anti-PD-1 therapy [Dendritic Cell]

| PRJNA934064 | ENA

Combinational targeting CCL7 and Flt3L to promote the expansion and infiltration of cDC1 in tumors enhances T cell activation and anti-PD-1 therapy [CD8 T]

Project description:Combinational targeting CCL7 and Flt3L to promote the expansion and infiltration of cDC1 in tumors enhances T cell activation and anti-PD-1 therapy [CD8 T]

| PRJNA934477 | ENA

Flt3L therapy induces a Treg‐promoting cDC1 state in triple‐negative breast cancer

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.

2023-07-26 | GSE225539 | GEO

Combinational targeting CCL7 and Flt3L to promote the expansion and infiltration of cDC1 in tumors enhances T cell activation and anti-PD-1 therapy

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-02-18 | GSE225164 | GEO

The clonal and molecular aetiology of Flt3L-mediated ‘emergency’ dendritic cell development

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.

2020-04-03 | GSE147977 | GEO

TCR profiling of whole MC38 tumors, treated with PBS + IgG , Cis + PBS + aPD-1, Cis + DCP-IL-12/FLT3L + IgG or Cis + DCP-IL-12/FLT3L + ɑPD-1.

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.

2023-09-19 | GSE228161 | GEO

Flt3L therapy induces a Treg‐promoting cDC1 state in triple‐negative breast cancer

Project description:Flt3L therapy induces a Treg‐promoting cDC1 state in triple‐negative breast cancer

| PRJNA936137 | ENA

Single cell expression profiling of whole B16F10 melanoma tumors, treated with PBS or DCP-IL-12/FLT3L.

2023-09-19 | GSE228014 | GEO