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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE230004 | GEO | 2023/04/19

REPOSITORIES: GEO

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

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.

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

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

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Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy

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

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Genetically-driven target tissue over-expression of CD40: A novel mechanism in autoimmune disease

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