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

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

PROVIDER: PRJNA393126 | ENA |

REPOSITORIES: ENA

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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.

2017-08-10 | GSE100808 | GEO

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

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Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade.

Project description: Not available

| S-EPMC5591072 | biostudies-literature

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2017-08-10 | GSE100809 | GEO

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

Project description:CTLA-4 is a clinically validated antibody target for cancer immunotherapy. Toxicity, which is linked to efficacy in available anti-CTLA-4 regimens has, however, restricted their use and precluded full therapeutic dosing. Here we describe and preclinically characterize a potentially safe and highly efficacious strategy to target CTLA-4. Intratumoral administration of an oncolytic Vaccinia virus, engineered to encode a novel Treg depleting, checkpoint-blocking, anti-CTLA-4 antibody and GM-CSF (VVGM-aCTLA4) achieved tumor-restricted CTLA-4 receptor saturation and Treg-depletion, and regressed diverse tumors spanning inflamed to immunologically ignorant microenvironments. Critically, intratumorally “ignited” antitumor immunity translated into stronger systemic expansion of tumor-specific CD8+ T cells compared with systemic anti-CTLA-4. In a clinically relevant mouse model resistant to systemic immune checkpoint blockade, i.t. VVGM-aCTLA4 synergized with anti-PD-1 to reject “cold” tumors. Based on our established proof-of-concept, a clinical trial evaluating i.t. VVGM-aCTLA4 (BT-001) alone and in combination with anti-PD-1 in metastatic or advanced solid tumors has commenced.

2022-02-08 | GSE176052 | GEO

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Enhanced CTLA-4 blockade anti-tumor immunity with APG-157 combination in a murine head and neck cancer

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The immune checkpoint B7x promotes tumor-infiltrating tregs and resistance to anti-CTLA-4 therapy.

Project description:Tumor cells inhibit the anti-tumor immune response by expressing immunomodulatory factors and recruiting immunosuppressive cells to their microenvironment. Regulatory T cells (Tregs) are a population of CD4+ T cells that are commonly found in tumors, promoting a tolerogenic microenvironment and aiding in tumor immune evasion. The immune checkpoint ligand B7x is widely expressed in a broad variety of tumor types and is often associated with greater Treg infiltration, but the mechanism by which B7x promotes tumor-infiltrating Tregs is unknown. Here, we recapitulate the B7x-mediated increase in Tregs in murine tumor models and show that B7x promotes conversion of conventional CD4+ T cells into potently suppressive Tregs. We found that B7x induces global transcriptomic changes in Tregs, driving these cells to adopt an activated and suppressive phenotype. Mechanistically, B7x increased Foxp3 transcriptional expression by modulating the Akt/Foxo signaling pathway. Further, we found that expression of B7x by tumor cells reduced the efficacy of anti-CTLA-4 in syngeneic murine models in a Treg-dependent manner, but this resistance phenotype was overcome by combination anti-B7x and anti-CTLA-4 treatment. Put together, B7x mediates a novel Treg-promoting pathway within tumors and is a promising candidate for combination immunotherapy.

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2023-11-10 | GSE243281 | GEO

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Project description:Intracranial B16 melanoma tumors isolated from C57Bl6 mice were analyzed by mRNAseq. Four experimental groups were analyzed: (1) Mice with intracranial tumors receiving IgG; (2) Mice with intracranial tumors receiving anti-PD-1 plus anti-CTLA-4 therapy; (3) Mice with intracranial plus extracranial tumors receiving IgG; (4) Mice with intracranial plus extracranial tumors receiving anti-PD-1 plus anti-CTLA-4 therapy. Taggart et al., PNAS 2018;

2018-02-01 | GSE109485 | GEO

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