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Gene Expression Profiling of human monocytes: Combination Therapy with Anti–CTLA-4 and Anti–PD-1 Leads to Distinct Immunologic Changes In Vivo

ABSTRACT: Transcriptome analysis of human peripheral blood monocytes Combination therapy concurrently targeting PD-1 and CTLA-4 immune checkpoints leads to remarkable antitumor effects. Although both PD-1 and CTLA-4 dampen the T cell activation, the in vivo effects of these drugs in humans remain to be clearly defined. To better understand biologic effects of therapy, we analyzed blood/tumor tissue from patients undergoing single or combination immune checkpoint blockade. We show that blockade of CTLA-4, PD-1, or combination of the two leads to distinct genomic (changes in gene-expression profile) and functional signatures in vivo in purified human T cells and monocytes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE77924 | GEO | 2016/02/16

SECONDARY ACCESSION(S): PRJNA312113

REPOSITORIES: GEO

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Gene Expression Profiling of human monocytes: Combination Therapy with AntiâCTLA-4 and AntiâPD-1 Leads to Distinct Immunologic Changes In Vivo

Project description:Transcriptome analysis of human peripheral blood monocytes Combination therapy concurrently targeting PD-1 and CTLA-4 immune checkpoints leads to remarkable antitumor effects. Although both PD-1 and CTLA-4 dampen the T cell activation, the in vivo effects of these drugs in humans remain to be clearly defined. To better understand biologic effects of therapy, we analyzed blood/tumor tissue from patients undergoing single or combination immune checkpoint blockade. We show that blockade of CTLA-4, PD-1, or combination of the two leads to distinct genomic (changes in gene-expression profile) and functional signatures in vivo in purified human T cells and monocytes. RNA extracted from freshly isolated monocytes from peripheral blood of patients treated with either antiâPD-1 (n = 6), antiâCTLA-4 (n = 5), Combo therapy with antiâPD-1 and antiâCTLA-4 concurrently (Combo, n = 6), and Seq antiâPD-1 in patients with prior antiâCTLA-4 (Seq, n = 3) was analyzed using the Affymetrix GeneChip Human Transcriptome 2.0 exon array. No techinical replicates were performed.

2016-02-16 | E-GEOD-77924 | biostudies-arrayexpress

Gene Expression Profiling of human T cells: Combination Therapy with Antiâ??CTLA-4 and Antiâ??PD-1 Leads to Distinct Immunologic Changes In Vivo

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2016-02-10 | E-GEOD-77714 | biostudies-arrayexpress

Gene Expression Profiling of human T cells: Combination Therapy with Anti–CTLA-4 and Anti–PD-1 Leads to Distinct Immunologic Changes In Vivo

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Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade [WES]

Project description:Immune checkpoint blockade is able to achieve durable responses in a subset of patients, however we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4 and anti-PD-1 induced tumor rejection. To address these issues we utilized mass cytometry to comprehensively profile the effects of checkpoint blockade on tumor immune infiltrates in human melanoma and murine tumor models. These analyses reveal a spectrum of tumor infiltrating T cell populations that are highly similar between tumor models and indicate that checkpoint blockade targets only specific subsets of tumor infiltrating T cell populations. Anti-PD-1 predominantly induces the expansion of specific tumor infiltrating exhausted-like CD8 T cell subsets. In contrast, anti-CTLA-4 induces the expansion of an ICOS+ Th1-like CD4 effector population in addition to engaging specific subsets of exhausted-like CD8 T cells. Thus, our findings indicate that anti-CTLA-4 and anti-PD-1 checkpoint blockade induced immune responses are driven by distinct cellular mechanisms.

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Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade [RNA-seq]

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Intratumoral anti-CTLA-4 delivery by an oncolytic Vaccinia virotherapy virus elicits CD8+ T cell immunity and synergizes with anti-PD-1 to reject “cold” tumors

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2023-11-10 | GSE243281 | GEO

RNAseq of tumor samples from CT26 syngeneic mouse treated with a PD-L1 and CTLA-4 immunotherapy combination

Project description:The ability to modulate immune-inhibitory pathways using checkpoint blockade antibodies such as PD-1, PD-L1, and CTLA-4 represents a significant breakthrough in cancer therapy in recent years. This has driven interest in identifying small-molecule-immunotherapy combinations to increase the proportion of responses. Murine syngeneic models, which have a functional immune system, represent an essential tool for pre-clinical evaluation of new immunotherapies. However, immune response varies widely between models and the translational relevance of each model is not fully understood, making selection of an appropriate pre-clinical model for drug target validation challenging. Utilizing RNAseq transcriptomic profiling, we have characterised the changes in gene regulatory pathways and immune populations in CT26 mice after treatment with the combination of anti-PD-L1 and anti-CTLA-4 antibodies. At day 7 post tumor implant, the pathways analysis of differentially expressed genes indicated an enrichment for migration of leukocytes in response to inflammation and communication between innate and adaptive immune cells. Similarly, analysis of upstream regulators suggested that lipopolysaccharide, IL-1B, TNF, IFNG, and NFKB1A pathways associated with inflammation were activated. At day 14, pathways related T-helper cell signalling pathways were upregulated. In addition, upstream regulators of the lipopolysaccharide and IFNG pathway, as well STAT1 and IL21 pathway were enriched, indicative of innate and adaptive immune response to inflammation.

2020-04-16 | E-MTAB-7777 | biostudies-arrayexpress

Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade

Project description:Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade

| PRJNA393126 | ENA

Reprogramming the Intrahepatic Cholangiocarcinoma Immune Microenvironment by Chemotherapy and CTLA-4 Blockade Enhances Anti-PD1 Therapy (scRNA-seq)

Project description:Intrahepatic cholangiocarcinoma (ICC) has limited therapeutic options and a dismal prognosis. Adding blockade of the PD1 pathway to gemcitabine/cisplatin chemotherapy has recently shown efficacy in biliary tract cancers but with low response rates. Here, we studied the effects of anti-CTLA-4 when combined with anti-PD1 and gemcitabine/cisplatin in orthotopic murine models of ICC. This combination therapy led to substantial survival benefits and reduction of morbidity in two aggressive ICC models that were resistant to immunotherapy alone. Gemcitabine/cisplatin treatment increased tumor-infiltrating lymphocytes and normalized the ICC vessels, and when combined with dual CTLA-4/PD1 blockade, increased the number of activated CD8+Cxcr3+IFNγ+ T cells. CD8+T cells were necessary for the therapeutic benefit because the efficacy was compromised when CD8+ T cells were depleted. Expression of Cxcr3 on CD8+ T cells is necessary and sufficient since CD8+ T cells from Cxcr3+/+ but not Cxcr3–/– mice rescued efficacy in T cell‒deficient mice. Finally, rational scheduling of anti-CTLA-4 “priming” with chemotherapy followed by anti-PD1 therapy achieved equivalent efficacy with reduced overall drug exposure. These data suggest that this combination approach should be clinically tested to overcome resistance to current therapies in ICC patients.

2024-01-18 | GSE253627 | GEO

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