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Inhibition of circulating glycocholic acid-regulated signaling potentiates immune checkpoint therapy in colorectal cancer

ABSTRACT: Inhibition of circulating glycocholic acid-regulated signaling potentiates immune checkpoint therapy in colorectal cancer

PROVIDER: PRJNA1006362 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25667353_1.fastq.gz	Fastqsanger.gz
	SRR25667353_2.fastq.gz	Fastqsanger.gz
	SRR25667354_1.fastq.gz	Fastqsanger.gz
	SRR25667354_2.fastq.gz	Fastqsanger.gz
	SRR25667355_1.fastq.gz	Fastqsanger.gz

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Inhibition of circulating glycocholic acid-regulated signaling potentiates immune checkpoint therapy in colorectal cancer

Project description:Serum bile acids (BAs) are an important risk factor for the initiation and progression of cancer, but their roles in colorectal cancer (CRC) remain largely unknown. The present study showed that glycocholic acid (GCA), a primary BA, was highly accumulated in the serum of patients with CRC. In a mouse model of CRC, GCA diet promoted programmed death-ligand 1 (PD-L1) expression in tumors, which attenuated CD8+ T cell-mediated antitumor responses in the tumor microenvironment (TME), and promoted the occurrence and development of CRC. Increased PD-L1 expression was caused by the reduction in activity of the BA receptor farnesoid X receptor (FXR). Mechanistically, FXR acted as transcriptional repressor for the transcription factor SRY-box transcription factor 14 (SOX14), and suppressed the palmitoylation and stabilization of PD-L1 by inhibiting the SOX14-mediated expression of zinc finger DHHC-type palmitoyl transferase 9 (DHHC9). Notably, genetically silencing SOX14 and DHHC9 in cancer cells or administering an FXR agonist synergized with anti-PD-1 therapy, leading to reduced tumor growth in GCA-fed mice. Together, the present findings reveal a previously unrecognized mechanism of BA in remodeling the TME to mediate CRC resistance to immunotherapy, which may have clinical implications for developing immunotherapy strategies for patients with CRC.

2024-08-17 | GSE241076 | GEO

The immune checkpoint regulator CD40 potentiates myocardial inflammation

Project description:The immune checkpoint regulator CD40 potentiates myocardial inflammation

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Autophagy Inhibition via Targeting of PIKfyve Potentiates Immune Checkpoint Blockade in Prostate Cancer Therapy

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Autophagy Inhibition via Targeting of PIKfyve Potentiates Immune Checkpoint Blockade in Prostate Cancer Therapy

Project description:To understand the tumor microenvironment changes in terms of transcriptome upon PIKfyve inhibition by small molecule ESK981 and the immune checkpoint inhibitor anti-PD-1 in Myc-CaP syngeneic mouse model.

2021-05-18 | GSE174644 | GEO

Melanoma cell intrinsic GABAA receptor enhancement potentiates radiation and immune checkpoint inhibitor response by promoting direct and T cell-mediated anti-tumor activity

Project description:Most metastatic melanoma patients show variable responses to radiotherapy and do not benefit from immune checkpoint inhibitors (ICIs). Improved strategies for combination therapy that leverage potential benefits from radiotherapy and ICI are critical. Genes coding for subunits of GABAARs express functional GABAARs in melanoma cells. By enhancing GABAAR mediated anion transport, benzodiazepines depolarize melanoma cells and impair their viability. In vivo, benzodiazepine alone reduces tumor growth and potentiates radiotherapy and α-PD-L1 anti-tumor activity. Combination of benzodiazepine, radiotherapy, and α-PD-L1 results in near complete regression of treated tumors and a potent abscopal effect, mediated by increased infiltration of polyfunctional CD8+ T cells. Treated tumors show expression of cytokine:cytokine receptor interactions and overrepresentation of p53 signaling. This study identifies an anti-tumor strategy combining radiation and/or immune checkpoint inhibitor with modulation of GABAARs in melanoma using a benzodiazepine.

2020-10-23 | GSE159829 | GEO

The immune checkpoint regulator CD40 potentiates myocardial inflammation

Project description:Immune checkpoint therapeutics including CD40 agonists have tremendous promise to elicit antitumor responses in patients resistant to current therapies. Conventional immune checkpoint inhibitors (PD-1/PD-L1, CTLA-4 antagonists) are associated with serious adverse cardiac events including life-threatening myocarditis. However, little is known regarding the potential for CD40 agonists to trigger myocardial inflammation or myocarditis. Here, we leverage genetic mouse models, single cell sequencing, and cell depletion studies to demonstrate that an anti-CD40 agonist antibody reshapes the cardiac immune landscape through activation of CCR2+ macrophages and subsequent recruitment of effector memory CD8 T-cells. We identify a positive feedback loop between CCR2+ macrophages and CD8 T-cells driven by IL12b, TNF, and IFN-γ signaling that promotes myocardial inflammation and show that prior exposure to CD40 agonists sensitizes the heart to secondary insults and accelerates LV remodeling. Collectively, these findings highlight the potential for CD40 agonists to promote myocardial inflammation and potentiate heart failure pathogenesis.

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PHGDH heterogeneity potentiates cancer cell dissemination and metastasis

Project description:Cancer metastasis requires the transient activation of cellular programs enabling dissemination and seeding in distant organs. Genetic, transcriptional and translational heterogeneity contributes to this dynamic process. Metabolic heterogeneity has also been observed, yet its role for cancer progression is less explored. Here, we discover that loss of phosphoglycerate dehydrogenase (PHGDH) potentiates metastatic dissemination. Specifically, we find that heterogeneous or low PHGDH expression in primary tumors of breast cancer patients is associated with decreased metastasis free survival time. In mice, circulating tumor cells and early metastatic lesions are enriched with PHGDH low cancer cells and silencing PHGDH in primary tumors increases metastasis formation. Mechanistically, PHGDH protein interacts with the glycolytic enzyme phosphofructokinase (PFK) and the loss of this interaction activates the hexosamine – sialic acid pathway, which provides precursors for protein glycosylation. Consequently, aberrant protein glycosylation including increased sialylation of integrin αvβ3 occurs, which potentiates cell migration and invasion. Inhibition of sialic acid metabolism counteracts the metastatic capacity of PHGDH low cancer cells. In conclusion, while the catalytic activity of PHGDH supports cancer cell proliferation, low PHGDH protein expression non-catalytically potentiates cancer dissemination and metastasis formation. Thus, the presence of PHDGH heterogeneity in primary tumors may be considered a sign of tumor aggressiveness.

2022-03-30 | GSE198380 | GEO

Inhibition of APOE potentiates immune checkpoint therapy for cancer.

Project description:Checkpoint immunotherapy is capable of unleashing T cells for controlling tumor, whereas it is destroyed by immunosuppressive myeloid cell. Apoprotein E (APOE) refers to a ligand in terms of the members of low-density lipoprotein (LDL) receptor family for mediating Apoprotein B-involving atherogenic lipoprotein clearance. Besides, tumor-infiltration macrophage can express APOE. The present study reported Apoe-/- mice to exhibit higher resistance toward the development of three types of carcinomas as compared with mice with wild type and to have greater responses to αPD-1 (anti-PD-1) immunotherapy. Moreover, treatment by exploiting APOE inhibitor (COG 133TFA, αAPOE) was capable of curbing tumor development and fostering regression if in combination of αPD-1. According to single-cell RNA sequencing (scRNA-seq), Apoe deletion was correlated with the decline of C1QC+ and CCR2+ macrophage within tumor infiltration, and mass spectrometry results noticeably showed down-regulated the number of M2 macrophages as well. Furthermore, APOE expression in cancer patients resistant to αPD-1 treatment significantly exceeded that in the sensitive group. For this reason, APOE is likely to be targeted for modifying tumor macrophage infiltrate and augmenting checkpoint immunotherapy.

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Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer.

Project description:Despite its success in achieving the long-term survival of 10-30% of treated individuals, immune therapy is still ineffective for most patients with cancer1,2. Many efforts are therefore underway to identify new approaches that enhance such immune 'checkpoint' therapy3-5 (so called because its aim is to block proteins that inhibit checkpoint signalling pathways in T cells, thereby freeing those immune cells to target cancer cells). Here we show that inhibiting PCSK9-a key protein in the regulation of cholesterol metabolism6-8-can boost the response of tumours to immune checkpoint therapy, through a mechanism that is independent of PCSK9's cholesterol-regulating functions. Deleting the PCSK9 gene in mouse cancer cells substantially attenuates or prevents their growth in mice in a manner that depends on cytotoxic T cells. It also enhances the efficacy of immune therapy that is targeted at the checkpoint protein PD1. Furthermore, clinically approved PCSK9-neutralizing antibodies synergize with anti-PD1 therapy in suppressing tumour growth in mouse models of cancer. Inhibiting PCSK9-either through genetic deletion or using PCSK9 antibodies-increases the expression of major histocompatibility protein class I (MHC I) proteins on the tumour cell surface, promoting robust intratumoral infiltration of cytotoxic T cells. Mechanistically, we find that PCSK9 can disrupt the recycling of MHC I to the cell surface by associating with it physically and promoting its relocation and degradation in the lysosome. Together, these results suggest that inhibiting PCSK9 is a promising way to enhance immune checkpoint therapy for cancer.

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A selective HDAC8 inhibitor potentiates antitumor immunity and efficacy of immune checkpoint blockade in hepatocellular carcinoma

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