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VEGF receptor inhibitor brivanib sensitizes chemotherapy by targeting cGAS to boost antitumor immunity

ABSTRACT: VEGF receptor inhibitor brivanib sensitizes chemotherapy by targeting cGAS to boost antitumor immunity

PROVIDER: PRJNA785581 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17097322_1.fastq.gz	Fastqsanger.gz
	SRR17097322_2.fastq.gz	Fastqsanger.gz
	SRR17097323_1.fastq.gz	Fastqsanger.gz
	SRR17097323_2.fastq.gz	Fastqsanger.gz
	SRR17097324_1.fastq.gz	Fastqsanger.gz

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VEGF receptor inhibitor brivanib sensitizes chemotherapy by targeting cGAS to boost antitumor immunity

Project description:Chemoresistance challenges the clinical application of most widely used platinum-based cancer chemotherapeutics which canonically function through inducing DNA damage. The DNA sensor cyclic GMP–AMP synthase (cGAS) connects genome instability to type I IFN response which confers vulnerability to platinum treatment. Here, by using a high throughput small-molecule-microarray-based screening of cGAS interacting compounds, we identified brivanib, known as an inhibitor of the vascular endothelial growth factor receptor (VEGFR), as a novel cGAS agonist. Brivanib markedly enhanced platinum-induced STING-TBK1-type I IFN response in tumor cells indispensable of cGAS. Importantly, brivanib synergizes the effect of cisplatin in restricting the growth of xenografted Lewis Lung Cancer (LLC) cells by boosting CD8+ T cell response in a cGAS-dependent manner. Mechanistically, brivanib enhances the DNA binding affinity of cGAS by directly targeting leucine 495 of cGAS. Moreover, leucine 495 of cGAS is essential for brivanib-mediated promoting effect on cisplatin-mediated type I IFN response and inhibition of tumor growth. Clinically, higher expression of cGAS in tumor renders a more favorable response to platinum-based chemotherapeutic regimens and better prognosis in lung cancer patient. Taken together, our findings discover cGAS as an unprecedented target of brivanib and provide a rationale for the combination of brivanib with platinum-based chemotherapeutics in cancer treatment.

2022-12-31 | GSE190016 | GEO

SETDB1-TRIM28 complex suppresses antitumor immunity [RNA-seq]

Project description:Epigenetic mechanism contributes to immune landscapes in cancer. Here we identify the SETDB1-TRIM28 complex as a critical suppressor of antitumor immunity. An epigenetic CRISPR-Cas9 screen of 1,218 chromatin regulators identified TRIM28 as a novel suppressor of PD-L1 expression. We revealed that expression of the SETDB1-TRIM28 complex negatively correlates with infiltration of effector CD8+ T cells. Inhibition of SETDB1-TRIM28 simultaneously upregulates PD-L1 and activates the cGAS-STING innate immune response to increase infiltration of CD8+ T cells. Mechanistically, SETDB1-TRIM28 inhibition leads to micronuclei formation in cytoplasm, a known activator of the cGAS-STING pathway. Thus, SETDB1-TRIM28 inhibition bridges the innate and adaptive immunity. Indeed, SETDB1 knockout enhances the antitumor effects of immune checkpoint blockade anti-PD-L1 in an ovarian cancer mouse model in a cGAS dependent manner. Our findings establish SETDB1-TRIM28 complex as a regulator of antitumor immunity and its loss activates cGAS-STING innate immunity to boost antitumor effects of immune checkpoint blockades.

2021-10-20 | GSE182089 | GEO

SETDB1-TRIM28 complex suppresses antitumor immunity [CRISPR/Cas9 screen]

2021-10-20 | GSE182197 | GEO

VEGF blockade enhances the antitumor effect of BRAFV600E inhibition

Project description:VEGF blockade enhances the antitumor effect of BRAFV600E inhibition

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Gene induction in STAT1-/- fibroblasts transduced with lentiviruses expressing human cGAS

Project description:The hypothesis tested was that lentiviral driven cGAS expression activates antiviral gene expression. Cells were transduced with lentiviruses expressing cGAS or a control (firefly luciferase). Total RNA was harvested 48 h post-transduction and processed for Illumina BeadArray.

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Nano-hijacked myeloid cells potentiate antitumor immunity and radiotherapy for glioblastoma

Project description:Abstract: Radiation therapy is a key component of the standard of care for glioblastoma (GBM). Although this treatment is known to trigger pro-inflammatory immune responses, it also results in several immune resistance mechanisms such as the upregulation of CD47 by tumors leading to avoidance of phagocytosis and the overexpression of PD-L1 in tumor-associated myeloid cells (TAMCs). Leveraging these RT-elicited processes, we generated a bispecific-lipid nanoparticle (B-LNP) that engaged TAMCs to glioma cells via anti-CD47/PD-L1 dual-ligation. We show that B-LNP blocked these two vital immune checkpoint molecules and promoted the phagocytic activity of TAMCs. In order to boost subsequent T cell recruitment and antitumor activity after tumor engulfment, the B-LNP was encapsulated with diABZI, a non-nucleotidyl agonist for stimulator of interferon genes (STING). In vivo treatment with the diABZI-loaded B-LNP induced a transcriptomic and metabolic switch in TAMCs, transforming them into potent antitumor effector cells, which induced T cell infiltration and activation of in the brain tumors. In preclinical murine glioma models, B-LNP therapy significantly potentiated the antitumor effects of radiotherapy, promoted brain tumor regression, and induced immunological memory against gliomas. The nano37 therapy was efficacious through both intra-tumoral and systemic delivery routes. In summary, our study shows a unique nanotechnology-based approach that hijacks multiple immune checkpoints to boost potent and long-lasting antitumor immunity against GBM.

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RNA sequencing of HUVECs stimulated with VEGF, OSM+VEGF, or CNTF+CNTFR+VEGF

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NK cell immune responses differ after prime and boost vaccination

Project description:A better understanding of innate responses induced by vaccination is critical for designing optimal vaccines. Here, we studied the diversity and dynamics of the NK cell compartment after prime-boost immunization with the modified vaccinia virus Ankara using cynomolgus macaques as a model. Mass cytometry was used to deeply characterize blood NK cells. The NK cell subphenotype composition was modified by the prime. Certain phenotypic changes induced by the prime were maintained over time and, as a result, the NK cell composition prior to boost differed from that before prime. The key phenotypic signature that distinguished NK cells responding to the boost from those responding to the prime included stronger expression of several cytotoxic, homing, and adhesion molecules, suggesting that NK cells at recall were functionally distinct. Our data reveal potential priming or imprinting of NK cells after the first vaccine injection. This study provides novel insights into prime-boost vaccination protocols that could be used to optimize future vaccines.

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