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Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer

ABSTRACT: Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer

PROVIDER: PRJNA728064 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14465526_1.fastq.gz	Fastqsanger.gz
	SRR14465526_2.fastq.gz	Fastqsanger.gz
	SRR14465527_1.fastq.gz	Fastqsanger.gz
	SRR14465527_2.fastq.gz	Fastqsanger.gz
	SRR14466027_1.fastq.gz	Fastqsanger.gz

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Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer [tumor]

Project description:Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer [tumor]

| PRJNA728069 | ENA

Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer [tumor]

Project description:Immune checkpoint blockade (ICB) has improved outcomes in some cancers. A major limitation of ICB is that a majority of patients fail to respond, which is partly attributable to immunosuppression. Obesity appears to improve immune checkpoint therapies in some cancers but impacts on breast cancer (BC) remain unknown. In obese mice fed an obesogenic or lean controls on a low fat diet, mice are injected with BC cells andtreated with anti-PD-1 or control. Obesity leads to immunosuppression systemically in tumor-free mice that is exacerbated in tumor-bearing mice. Obesity augments tumor incidence and progression. Anti-PD-1 induces regression in lean mice and potently abrogates progression in obese mice. Anti PD-1 significantly reduces immunosuppressive cells and elevates anti-tumor immune cells. Lamb2, downregulated by anti-PD1, significantly predict patient survival. Last, we identify a microbial signature associated with anti-PD-1 efficacy. In sum, anti-PD-1 is highly efficacious in obese mice by reinvigorating durable antitumor immunity.

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Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer [Mammary fat pad, MFP]

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Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer [Mammary fat pad, MFP]

Project description:Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer [Mammary fat pad, MFP]

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Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer.

Project description:Immune checkpoint blockade (ICB) has improved outcomes in some cancers. A major limitation of ICB is that most patients fail to respond, which is partly attributable to immunosuppression. Obesity appears to improve immune checkpoint therapies in some cancers, but impacts on breast cancer (BC) remain unknown. In lean and obese mice, tumor progression and immune reprogramming were quantified in BC tumors treated with anti-programmed death-1 (PD-1) or control. Obesity augments tumor incidence and progression. Anti-PD-1 induces regression in lean mice and potently abrogates progression in obese mice. BC primes systemic immunity to be highly responsive to obesity, leading to greater immunosuppression, which may explain greater anti-PD-1 efficacy. Anti-PD-1 significantly reinvigorates antitumor immunity despite persistent obesity. Laminin subunit beta-2 (Lamb2), downregulated by anti-PD-1, significantly predicts patient survival. Lastly, a microbial signature associated with anti-PD-1 efficacy is identified. Thus, anti-PD-1 is highly efficacious in obese mice by reinvigorating durable antitumor immunity. VIDEO ABSTRACT.

| S-EPMC8574993 | biostudies-literature

Immune checkpoint blockade unleashes aberrant immune responses against the microbiota

Project description:Immune checkpoint blockade unleashes aberrant immune responses against the microbiota

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Melanoma Sequential Immune Checkpoint Blockade Treatment Sequencing Study

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Immune checkpoint blockade unleashes aberrant immune responses against the microbiota

Project description:Immune checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4 are essential components of the cancer therapeutic armamentarium. The remarkable responses seen with ICIs however, are also accompanied by immune-related adverse events (irAEs). These inflammatory side-effects impact virtually all organ systems, with the most common being the skin and gastrointestinal tract. Here, we establish a mouse model of commensal bacteria-driven skin irAEs and demonstrate that immune checkpoint blockade aberrantly unleashes commensal-specific T cell responses. Such responses caused widespread immune cell infiltration and inflammation throughout the skin, recapitulating the skin irAEs seen in patients treated with ICIs. This skin inflammation was dependent on production of the cytokine IL-17 by commensal-specific T cells, which in turn induced hyperactive responses from macrophages and myeloid cells. Importantly, these responses had long-term consequences, with commensal-specific T cells elicited in the context of ICIs being highly sensitive to re-activation by commensals months later. Together, our results establish a mouse model of skin irAEs and show that immune checkpoint blockade can potentiate aberrant immunity to skin commensals with long-lasting consequences.

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Combinatorial high throughput drug screening identifies a synergistic drug interaction that sensitizes mesenchymal pancreatic cancer to immune checkpoint blockade

Project description:KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) is highly immunosuppressive and resistant to targeted therapies, immune checkpoint blockade and engineered T cells. Here, we performed a systematic high throughput combinatorial drug screen and identified a synergistic interaction between the MEK inhibitor trametinib and the multi-kinase inhibitor nintedanib. This interaction targets KRAS-directed oncogenic signaling in the aggressive and therapy resistant non-glandular mesenchymal subtype of PDAC, driven by an allelic imbalance, increased gene-dosage and expression of oncogenic KRAS. Mechanistically, the combinatorial treatment induces cell cycle arrest and cell death and initiates an interferon response. Using single cell RNA sequencing and immunophenotyping, we show that the combination therapy reprograms the immunosuppressive microenvironment and primes cytotoxic and memory T cells to infiltrate the tumors, thereby sensitizing mesenchymal PDAC to PD-L1 inhibition. This work opens new avenues to target the therapy refractory mesenchymal PDAC subtype.

2022-02-11 | PXD027877 | Pride

Combinatorial high throughput drug screening identifies a synergistic drug interaction that sensitizes mesenchymal pancreatic cancer to immune checkpoint blockade

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