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An engineered mycobacterium smegmatis expressing anti-PD-L1/IL-15 immunocytokine induces and activates specific antitumor immunity

ABSTRACT: An engineered mycobacterium smegmatis expressing anti-PD-L1/IL-15 immunocytokine induces and activates specific antitumor immunity

PROVIDER: PRJNA1176547 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31093890_1.fastq.gz	Fastqsanger.gz
	SRR31093890_2.fastq.gz	Fastqsanger.gz
	SRR31093891_1.fastq.gz	Fastqsanger.gz
	SRR31093891_2.fastq.gz	Fastqsanger.gz
	SRR31093892_1.fastq.gz	Fastqsanger.gz

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An engineered mycobacterium smegmatis expressing anti-PD-L1/IL-15 immunocytokine induces and activates specific antitumor immunity

Project description:Immune checkpoint inhibitors and cytokines have revolutionized tumor treatment but are still limited by dose-dependent toxicity and efficacy. In situ vaccine platforms based on intelligent microbes are promising therapeutic strategies, which can sustainably deliver drugs locally without causing severe systemic risks. Here, we have innovatively engineered a nonpathogenic, adjuvant-acting Mycobacterium smegmatis (M. smegmatis) that coexpresses a PD-L1 inhibitor and an IL-15 cytokine complex containing the IL-15Rα sushi domain (Ms-PDL1scfv-IL15). We demonstrate that PD-L1 inhibitor and IL-15 secretion systemically binds mouse or human PD-L1 and maintains IL-15 stimulatory activity. The bifunctional Ms-PDL1scfv-IL15 overcomes resistance to PD-L1 blockade, recruits numerous immune cells in situ, induces dendritic cells (DCs) maturation, initiates the M1 anti-tumor polarization of macrophages, increases the proliferation and activation of NK cells and tumor-infiltrating CD8+ T cells, inhibits the Tregs, elicits abscopal effects, stimulates rapid tumor regression, prevents metastasis, and leads to long-term survival in several syngeneic tumor mouse models. We also found that the combination of Ms-PDL1scfv-IL15 with GM–CSF synergistically stunted the tumor progress and stasis. Moreover, intratumoral administration of Ms-PDL1scfv-IL15 can capture tumor antigen fragments, and boost DCs presentation of antigens, which remarkably initiates tumor antigen-specific immune response, leading to durable tumor regression and specific antitumor immunity. In summary, this engineered M. smegmatis to recruit and activate innate and adaptive antitumor immune responses, offering a potent cancer immunotherapy strategy to treat patients with cold tumors or resistance to checkpoint blockade.

2024-12-25 | GSE280146 | GEO

RNA-seq of Mycobacteriophage Island3 infection of Mycolicibacterium smegmatis mc2155, Mycolicibacterium smegmatis mc2155(Butters), and Mycolicibacterium smegmatis mc2155(Buttersgp57r)

Project description:RNA-seq of Mycobacteriophage Island3 infection of Mycolicibacterium smegmatis mc2155, Mycolicibacterium smegmatis mc2155(Butters), and Mycolicibacterium smegmatis mc2155(Buttersgp57r) to assess the impact of Butters lysogen and specifically Buttersgp57r on transcript levels of island3 during infection.

2022-12-24 | GSE221406 | GEO

A novel anti-PD-L1/IL-15 immunocytokine overcomes resistance to PD-L1 blockade and elicits potent antitumor immunity.

Project description:Despite the demonstrated immense potential of immune checkpoint inhibitors in various types of cancers, only a minority of patients respond to these therapies. Immunocytokines designed to deliver an immune-activating cytokine directly to the immunosuppressive tumor microenvironment (TME) and block the immune checkpoint simultaneously may provide a strategic advantage over the combination of two single agents. To increase the response rate to checkpoint blockade, in this study, we developed a novel immunocytokine (LH01) composed of the antibody against programmed death-ligand 1 (PD-L1) fused to interleukin (IL)-15 receptor alpha-sushi domain/IL-15 complex. We demonstrate that LH01 efficiently binds mouse or human PD-L1 and maintains IL-15 stimulatory activity. In syngeneic mouse models, LH01 showed improved antitumor efficacy and safety versus anti-PD-L1 plus LH02 (Fc-sushi-IL15) combination and overcame resistance to anti-PD-L1 treatment. Mechanistically, the dual anti-immunosuppressive function of LH01 activated both the innate and adaptive immune responses and induced a favorable and immunostimulatory TME. Furthermore, combination therapy with LH01 and bevacizumab exerts synergistic antitumor effects in an HT29 colorectal xenograft model. Collectively, our results provide supporting evidence that fusion of anti-PD-L1 and IL-15 might be a potent strategy to treat patients with cold tumors or resistance to checkpoint blockade.

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Characterization of Mycobacterium smegmatis SigF regulon

Project description:Mycobacterium smegmatis SigF is a group III sigma factor. Its ortholog in M. tuberculosis is reported to have role in regulation and function of cell wall components. In present study we have created an M. smegmatis ΔsigF mutant by allele exchange method. M. smegmatis sigF mutant shows non pigmented phenotype and is more sensitive to hydrogen peroxide generated oxidative stress. DNA microarray analysis of M. smegmatis wild type and ΔsigF mutant suggests that SigF in this species controls the expression of several energy and central intermediary metabolism genes along with regulation of carotenoid biosynthesis.

2010-08-20 | GSE19774 | GEO

The immunocytokine PD1-IL2v overcomes resistance to tumor immunity, and synergizes with anti-PD-L1

Project description:Immunotherapies have shown remarkable, albeit tumor-selective therapeutic benefits in the clinic. Here we evaluated the effects of the immunocytokine PD1-IL2v in a mouse model of de novo pancreatic neuroendocrine cancer resistant to checkpoint and other immunotherapies. PD1-IL2v is a bi-specific molecule based on a bivalent PD-1 antibody, serving as a targeting moiety, fused to an immuno-stimulatory IL-2 variant (IL2v) to precisely deliver IL2v to PD-1+ T-cells in the tumor microenvironment. PD1-IL2v elicited dramatic infiltration by CD8 T cells, notably stem-like and effector memory T cells, resulting in tumor regression and enhanced survival in mice. Furthermore, combining anti-PD-L1 with PD1-IL2v sustained the response phase, improving therapeutic efficacy both by reprogramming immunosuppressive tumor-associated macrophages and tumor endothelial cells , and by enhancing TCR immune repertoire diversity. The data motivate consideration of clinical trials to evaluate the combination therapy of PD1-IL2v and anti-PD-L1, especially in immunotherapy-resistant tumors infiltrated with PD-1+ T stem-like CD8 T cells.

2023-01-10 | GSE197854 | GEO

Cholesterol chemostat M. smegmatis

Project description:M. smegmatis grown on cholesterol or glycerol in continous culture at a dilution rate of 0.01 h-1.

2016-01-01 | GSE71818 | GEO

Mycolicibacterium smegmatis

Project description:Mycolicibacterium smegmatis Proteome

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Mycolicibacterium smegmatis

Project description:Mycolicibacterium smegmatis Genome sequencing

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RNAseq of LepA knock-out in M. smegmatis

Project description:Expression profiling in LepA knock-out in M. smegmatis

2021-01-07 | GSE126130 | GEO

M. smegmatis pruR::Tn611 mutant (MB100pruR)

Project description:Transcriptional profiling of M. smegmatis MB100pruR vs. MB100 (isogenic parent) grown in serumvials on Hartmans de Bont medium supplemented with glycerol and proline

2012-05-01 | GSE20362 | GEO

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