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Anti-PD-1/anti-CTLA-4 efficacy in melanoma brain metastases depends on extracranial disease and augmentation of CD8+ T cell trafficking

ABSTRACT: Anti-PD-1/anti-CTLA-4 efficacy in melanoma brain metastases depends on extracranial disease and augmentation of CD8+ T cell trafficking

PROVIDER: PRJNA431187 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6502840.fastq.gz	Fastqsanger.gz
	SRR6502841.fastq.gz	Fastqsanger.gz
	SRR6502842.fastq.gz	Fastqsanger.gz
	SRR6502833.fastq.gz	Fastqsanger.gz
	SRR6502843.fastq.gz	Fastqsanger.gz

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Anti-PD-1/anti-CTLA-4 efficacy in melanoma brain metastases depends on extracranial disease and augmentation of CD8+ T cell trafficking

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

Anti-PD-1/anti-CTLA-4 efficacy in melanoma brain metastases depends on extracranial disease and augmentation of CD8<sup>+</sup> T cell trafficking.

Project description:Inhibition of immune checkpoints programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) on T cells results in durable antitumor activity in melanoma patients. Despite high frequency of melanoma brain metastases (BrM) and associated poor prognosis, the activity and mechanisms of immune checkpoint inhibitors (ICI) in metastatic tumors that develop within the "immune specialized" brain microenvironment, remain elusive. We established a melanoma tumor transplantation model with intracranial plus extracranial (subcutaneous) tumor, mimicking the clinically observed coexistence of metastases inside and outside the brain. Strikingly, intracranial ICI efficacy was observed only when extracranial tumor was present. Extracranial tumor was also required for ICI-induced increase in CD8+ T cells, macrophages, and microglia in brain tumors, and for up-regulation of immune-regulatory genes. Combined PD-1/CTLA-4 blockade had a superior intracranial efficacy over the two monotherapies. Cell depletion studies revealed that NK cells and CD8+ T cells were required for intracranial anti-PD-1/anti-CTLA-4 efficacy. Rather than enhancing CD8+ T cell activation and expansion within intracranial tumors, PD-1/CTLA-4 blockade dramatically (∼14-fold) increased the trafficking of CD8+ T cells to the brain. This was mainly through the peripheral expansion of homing-competent effector CD8+ T cells and potentially further enhanced through up-regulation of T cell entry receptors intercellular adhesion molecule 1 and vascular adhesion molecule 1 on tumor vasculature. Our study indicates that extracranial activation/release of CD8+ T cells from PD-1/CTLA-4 inhibition and potentiation of their recruitment to the brain are paramount to the intracranial anti-PD-1/anti-CTLA-4 activity, suggesting augmentation of these processes as an immune therapy-enhancing strategy in metastatic brain cancer.

| S-EPMC5816160 | biostudies-literature

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]

2017-08-10 | GSE100807 | GEO

Transcriptome of YTN16 tumor tissues after treatment with anti-PD-L1 or anti-CTLA-4

Project description:A murine gastric cancer YTN16 is sensitive to anti-CTLA-4, but resistant to anti-PD-L1. To investigate tumor microenvironments after treatment of these mAbs, we performed RNA-Seq analyses.

2022-01-19 | GSE184092 | GEO

Immune response biomarker profiling of serum from prostate cancer patients treated with anti-CTLA-4 immunotherapy.

Project description:Anti-CTLA-4 induced antibody responses to antigens in prostate cancer patients. Pre-treatment and post-treatment sera from 5 clinical responders and 6 clinical non-responders were used to hybridize protein arrays.

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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

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

Immune response biomarker profiling of serum from prostate cancer patients treated with anti-CTLA-4 immunotherapy.

Project description:Anti-CTLA-4 induced antibody responses to antigens in prostate cancer patients.

2012-11-05 | GSE39688 | GEO

Efficacious anti-CTLA-4 antibodies drive myeloid activation and TME reprograming through FcγR engagement and Type-I interferon signaling

Project description:Despite the clinical success of checkpoints inhibitors, a significant gap still exists in our understanding of their in vivo mechanism of action, thus limiting the rational development of next generation agents. Amongst these, anti-CTLA-4 antibodies were originally developed to block inhibitory signals into activated effector T cells. However, several recent studies have demonstrated that depletion of regulatory T cells expressing high levels of CTLA-4 is critical to anti-CTLA-4 anti-tumor activity. Whereas the mechanism of action remains controversial, the emerging data support clinical development of new antibodies with enhanced killing activity. Here, using single-cell RNA sequencing in in vivo and in vitro mouse models, we sought to dissect the impact of anti-CTLA-4 blocking, Treg depleting, and FcR engaging activity on the immune responses within tumors. We observed a rapid remodeling of the innate immune landscape as early as 24-hours post-treatment. Immune remodeling was driven mainly by FcγR-engagement, and not by Treg depletion or CTLA-4 blockade, and included reduction of suppressive macrophages and activation of type-I interferon signaling. Our findings indicate that FcγR engagement and innate immune remodeling are involved in successful anti-CTLA-4 treatment, supporting further development of optimized immunotherapy agents with these features.

2022-08-11 | GSE186484 | GEO

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

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