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Combinatorial immunotherapy with agonistic CD40 activates dendritic cells to express IL-12 and overcome PD-1 resistance

ABSTRACT: Combinatorial immunotherapy with agonistic CD40 activates dendritic cells to express IL-12 and overcome PD-1 resistance

PROVIDER: PRJNA956950 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24206922.fastq.gz	Fastqsanger.gz
	SRR24206923.fastq.gz	Fastqsanger.gz

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Combinatorial immunotherapy with agonistic CD40 activates dendritic cells to express IL-12 and overcome PD-1 resistance II

Project description:Combinatorial immunotherapy with agonistic CD40 activates dendritic cells to express IL-12 and overcome PD-1 resistance II

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Combinatorial immunotherapy with agonistic CD40 activates dendritic cells to express IL-12 and overcome PD-1 resistance

Project description:Checkpoint inhibitors have revolutionized cancer treatment, but resistance remains a significant clinical challenge. Myeloid cells within the tumor microenvironment can modulate checkpoint resistance by either supporting or suppressing adaptive immune responses. Using an anti-PD-1 resistant mouse melanoma model, we show that targeting the myeloid compartment via CD40 activation and CSF1R blockade in combination with anti-PD-1 results in complete tumor regression in a majority of mice. This triple therapy combination is primarily CD40 agonist-driven in the first 24 hours post-therapy and shows a similar systemic cytokine profile in human patients as in mice. Functional single-cell cytokine secretion profiling of dendritic cells (DCs) using a novel microwell assay identified a CCL22+CCL5+ IL-12-secreting DC subset as important early-stage effectors of triple therapy. CD4+ and CD8+ T cells are both critical effectors of treatment, and systems analysis of single-cell RNA-sequencing data supports a role for DC-secreted IL-12 in priming T cell activation and recruitment. Finally, we show that treatment with a novel IL-12 mRNA therapeutic alone is sufficient to overcome PD-1 resistance and cause tumor regression. Overall, we conclude that combining myeloid-based innate immune activation and enhancement of adaptive immunity is a viable strategy to overcome anti-PD-1 resistance.

2023-04-19 | GSE230004 | GEO

Combinatorial immunotherapy with agonistic CD40 activates dendritic cells to express IL-12 and overcome PD-1 resistance II

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Transcriptomic analysis of 4NQO-induced oral squamous cell carcinoma with agonistic anti-CD40 treatment

Project description:To investigate the anti-tumor effect of agonistic anti-CD40, 4NQO-indued OSCC mice with agonistic anti-CD40.

2023-10-23 | GSE217407 | GEO

IL-15 complex enhances agonistic anti-CD40 + anti-PDL1 by correcting the T-bet to Tox ratio in CD8+ T cells infiltrating pancreatic ductal adenocarcinoma

Project description:Single cell RNA sequencing paired with single cell V(D)J sequenction of immune cells infiltrating orthotopic KPC2a tumors, spleen cells, and CD8 T cells enriched from spleen cells on day 14 posttumor. Cohorts received no treatment, agonistic anti-CD40, anti-PD-L1 or the combination of agonistic anti-CD40 + anti-PDL1. Treatments were initated on day 7 posttumor.

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Bispecific antibodies increase the therapeutic window of CD40 agonists through selective dendritic cell targeting

Project description:Therapeutic use of agonistic anti-CD40 antibodies is a potentially powerful approach for activating the immune response to eradicate tumors. However, the translation of this approach to clinical practice has been significantly restricted due to the severe dose-limiting toxicities observed in multiple clinical trials. Here, we demonstrate that conventional type-1 dendritic cells are essential for triggering antitumor immunity but not toxicity by CD40 agonists, while macrophages, platelets, and monocytes lead to the toxic events. Therefore, we designed bispecific antibodies that target CD40 activation preferentially to dendritic cells. These bispecific reagents demonstrate a superior safety profile compared to their parental CD40 monospecific antibody, while triggering potent anti-tumor activity. We suggest such cell-selective bispecific agonistic antibodies as a drug platform to bypass the dose-limiting toxicities of anti-CD40, and of additional types of agonistic antibodies used for cancer immunotherapy.

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Cd40

Project description:Rattus norvegicus Cd40, CD40 molecule [Source:RGD Symbol;Acc:619830], is expressed in 4 baseline experiment(s);

| ENSRNOG00000018488 | ExpressionAtlas

Cd40

Project description:Rattus norvegicus Cd40, CD40 molecule [Source:RGD Symbol;Acc:619830], is differentially expressed in 22 experiment(s);

| ENSRNOG00000018488 | ExpressionAtlas

CD40

Project description:Sus scrofa CD40, CD40 molecule [Source:VGNC Symbol;Acc:VGNC:95545], is differentially expressed in 3 experiment(s);