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Formate supplementation enhances anti-tumor CD8+ T cell fitness and efficacy of PD-1 blockade

ABSTRACT: Formate supplementation enhances anti-tumor CD8+ T cell fitness and efficacy of PD-1 blockade

PROVIDER: PRJNA1003017 | ENA |

REPOSITORIES: ENA

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Formate supplementation enhances anti-tumor CD8+ T cell fitness and efficacy of PD-1 blockade

Project description:Metabolic support of the response to immune checkpoint blockage is unknown. We used scRNA-seq to determine the response of CD8+ cells to metabolic supplementation with the one carbon donor formate in combination with anti-PD-1

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Supplementation with α-ketoglutarate improved the efficacy of anti-PD1 melanoma treatment through epigenetic modulation of PD-L1

Project description:Patients with advanced melanoma have shown an improved outlook after receiving anti-PD1 therapy, but the low response rate restricts clinical benefit; therefore, enhancing anti-PD1 therapy efficacy remains a major challenge. Here, our findings show significantly higher abundance of α-KG in healthy controls, anti-PD1-sensitive melanoma-bearing mice, and anti-PD1-sensitive melanoma patients; moreover, supplementation with α-KG enhanced the efficacy of anti-PD1 immunotherapy and increased PD-L1 expression in melanomas via STAT1/3. We also found that supplementation with α-KG significantly increased methylcytosine dioxygenase TET2/3, which led to an increased 5-hydroxymethylcytosine (5-hmC) level in the PD-L1 promoter. As a consequence, STAT1/3 had been recognized and stabilized in PD-L1 promoter to upregulate PD-L1 expression. Importantly, single-cell sequencing of preclinical samples and analysis of clinical data revealed that the TET2/3-STAT1/3-CD274 signaling was associated with sensitivity to anti-PD1 treatment in melanoma. Taken together, we provide a novel insight into α-KG's function in melanoma anti-PD1 treatment and supplement of α-KG is a novel promising strategy to improve the efficacy of anti-PD1 therapy.

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Enhanced efficacy of simultaneous PD-1 and PD-L1 immune checkpoint blockade in high grade serous ovarian cancer [bulk RNA-seq tumor]

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Batf3-dendritic cells and 4-1BB/4-1BB ligand axis are required at the effector phase within the tumor microenvironment for PD-1/PD-L1 blockade efficacy

Project description:The cellular source of positive signals that reinvigorate T cells within the tumor microenvironment (TME) for the therapeutic efficacy of PD-1/PD-L1 blockade has not been clearly defined. We now show that Batf3-lineage dendritic cells (DCs) are essential in this process. Flow cytometric analysis, gene-targeted mice, and blocking antibody studies revealed that 4-1BBL was a major positive costimulatory signal provided by these DCs within the TME, that translated to CD8+ T cell functional reinvigoration and tumor regression. Immunofluorescence and spatial transcriptomics on human tumor samples revealed clustering of Batf3+ DCs and CD8+ T cells, which correlated with anti-PD-1 efficacy. In addition, proximity to Batf3+ DCs within the TME was associated with CD8+ T cell transcriptional states linked to anti-PD-1 response. Our results demonstrate that Batf3+ DCs within the TME are critical for PD-1/PD-L1 blockade efficacy, and indicate a major role for the 4-1BB/4-1BBL axis during this process.

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TNF blockade uncouples toxicity and anti-tumor efficacy induced with an agonist CD40 antibody

Project description:TNF mechanistically links cytokine release and hepatotoxicity triggered by an agonist CD40 antibody, and toxicity can be suppressed by blockade of TNF without affecting anti-tumor efficacy.

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FOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy [human_FOXO1_TCF7_OE_RNAseq]

Project description:FOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy [human_FOXO1_TCF7_OE_RNAseq]

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