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SN-38, an active metabolite of irinotecan, enhances anti-PD1 treatment efficacy in head and neck squamous cell carcinoma

ABSTRACT: Anti-programmed cell death 1 (PD-1) therapy shows definite but modest activity in patients with advanced/metastatic HNSCC. Preliminary evidence suggests that SN-38, an activated form of irinotecan that activates the transcription factor FoxO3a, may suppress the expression of PD-L1 in breast and ovarian tumor models. Here, we explore the efficacy of SN-38 in combination with anti-PD1 for HNSCC treatment. In vitro, SN-38 enhances FoxO3a expression and reduces the expression of PD-L1 dose-dependently in HNSCC cells. Low dose SN-38 increases interferon- excretion by natural killer (NK) cells and promotes NK cell-mediated cytotoxicity of tumor cells. In vivo studies reveal that, at non-cytotoxic drug concentrations, SN-38 significantly enhances anti-PD-1 activity in suppressing murine tumor growth. An increased infiltration of CD8+ T cells and NK cells was found in the post-treatment tumors. RNA-seq analysis confirms that SN-38 promotes the enrichment of immune cells and biological function genes related to the immune response became abundant in SN-38 and anti-PD1 treated tumors. Thus, SN-38 is a potentially beneficial adjunct to checkpoint inhibitor therapy in HNSCC. Further studies to explore its mechanism of action and possible application are mandatory.

ORGANISM(S): Mus musculus

PROVIDER: GSE222450 | GEO | 2023/01/11

REPOSITORIES: GEO

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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.

2023-03-08 | GSE223110 | GEO

Global hypomethylation mediated changes regulate constitutive PD-L1 expression in melanoma [RRBS]

Project description:PD-L1 is a ligand for the inhibitory PD1 receptor on T cells and its expression in some cancers inhibits anti-cancer immune response. In melanoma, PD-L1 expression is induced in response to immune stimuli but in a proportion of melanomas it is constitutively expressed. Factors that drive constitutive expression of PD-L1 are unknown. Here we performed genome-scale methylation analysis of six cell lines that constitutively express PD-L1 (PD-L1 positive, referred to as PD-L1CON) and six cell lines that only express PD-L1 after treatment with IFN- (PD-L1 negative, referred to as PD-L1IND)

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Global hypomethylation mediated changes regulate constitutive PD-L1 expression in melanoma [RNA-Seq]

Project description:PD-L1 is a ligand for the inhibitory PD1 receptor on T cells and its expression in some cancers inhibits anti-cancer immune response. In melanoma, PD-L1 expression is induced in response to immune stimuli but in a proportion of melanomas it is constitutively expressed. Factors that drive constitutive expression of PD-L1 are unknown. Here we performed RNA-Seq analysis of six cell lines that constitutively express PD-L1 (PD-L1 positive, referred to as PD-L1CON) and six cell lines that only express PD-L1 after treatment with IFN- (PD-L1 negative, referred to as PD-L1IND)

2018-05-24 | GSE107620 | GEO

The immunocytokine PD1-IL2v overcomes resistance to tumor immunity, and synergizes with anti-PD-L1

Project description:Immunotherapies have shown remarkable, albeit tumor-selective therapeutic benefits in the clinic. Here we evaluated the effects of the immunocytokine PD1-IL2v in a mouse model of de novo pancreatic neuroendocrine cancer resistant to checkpoint and other immunotherapies. PD1-IL2v is a bi-specific molecule based on a bivalent PD-1 antibody, serving as a targeting moiety, fused to an immuno-stimulatory IL-2 variant (IL2v) to precisely deliver IL2v to PD-1+ T-cells in the tumor microenvironment. PD1-IL2v elicited dramatic infiltration by CD8 T cells, notably stem-like and effector memory T cells, resulting in tumor regression and enhanced survival in mice. Furthermore, combining anti-PD-L1 with PD1-IL2v sustained the response phase, improving therapeutic efficacy both by reprogramming immunosuppressive tumor-associated macrophages and tumor endothelial cells , and by enhancing TCR immune repertoire diversity. The data motivate consideration of clinical trials to evaluate the combination therapy of PD1-IL2v and anti-PD-L1, especially in immunotherapy-resistant tumors infiltrated with PD-1+ T stem-like CD8 T cells.

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Project description:Therapeutic checkpoint antibodies blocking PD1/PD-L1 signaling have radically improved clinical outcomes in cancer. However, the regulation of PD-L1 expression on tumor cells is still poorly understood. Here we show that intra-tumoral copper levels influence PD-L1 expression in cancer cells. Copper supplementation enhanced PD-L1 expression at mRNA and protein levels in cancer cells and RNAseq revealed that copper regulates key signaling pathways mediating PD-L1-driven cancer immune evasion. Conversely, copper chelators inhibited phosphorylation of STAT3 and EGFR and promoted ubiquitin-mediated degradation of PD-L1. Overall, this study reveals an important role for copper in regulating PD-L1 and suggests that anti-cancer immunotherapy might be enhanced by pharmacologically reducing intra-tumor copper levels.

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Project description:The objective was to determine if there are differences in gene expression in PD-L1+ and PD-L1- NK cells after co-incubation of NK cells with target K562 myeloid leukemia cells.

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Project description:BET inhibitors (BETi) target bromodomain-containing proteins and are currently being evaluated as anti-cancer agents. We discovered that the maximal therapeutic effects of BETi in a Myc-driven B cell lymphoma model required an intact host immune system. Genome-wide analysis of the BETi induced transcriptional response identified the immune checkpoint ligand Cd274 (Pd-l1) as a Myc-independent, BETi target-gene. BETi directly repressed constitutively expressed and IFN-γ induced CD274 expression across different human and mouse tumor cell lines and primary patient samples. Mechanistically, BETi decreased Brd4 occupancy at the Cd274 locus without any change in Myc occupancy, resulting in transcriptional pausing and rapid loss of Cd274 mRNA production. Finally, targeted inhibition of the PD1/PD-L1 axis by combining anti-PD1 antibodies and the BETi JQ1 caused synergistic responses in mice bearing Myc-driven lymphomas. Our data uncovers a novel interaction between BETi and the PD-1/PD-L1 immune-checkpoint and provides novel insight into the transcriptional regulation of CD274.

2017-02-01 | GSE94133 | GEO

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