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Preclinical evaluation of the efficacy of anti-human SIRPα antibody for cancer immunotherapy using the MITRG humanized mouse model

ABSTRACT: Preclinical evaluation of the efficacy of anti-human SIRPα antibody for cancer immunotherapy using the MITRG humanized mouse model

PROVIDER: PRJNA1000579 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25467477_1.fastq.gz	Fastqsanger.gz
	SRR25467477_2.fastq.gz	Fastqsanger.gz
	SRR25467478_1.fastq.gz	Fastqsanger.gz
	SRR25467478_2.fastq.gz	Fastqsanger.gz
	SRR25467479_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Preclinical evaluation of the efficacy of anti-human SIRPα antibody for cancer immunotherapy using the MITRG humanized mouse model

Project description:Tumor-associated macrophages (TAMs) represent abundantly in the tumor microenvironment (TME) and are thought to be novel targets for cancer immunotherapy. To elucidate the antitumor effects of therapeutics targeting human TAMs in vivo, we have here established a preclinical tumor xenograft model using immunodeficient mice expressing multiple human cytokines (MITRG mice) and examined the anti-tumor effect of anti–human SIRPα antibodies SE12C3, which inhibit the interaction of CD47 on tumor cells and enhance Fcγ receptor-mediated phagocytosis of tumor cells by human macrophages. Humanized immune system (HIS)–MITRG mice particularly facilitate human macrophage differentiation following transplantation of human CD34+ hematopoietic stem and progenitor cells. HIS–MITRG mice promoted the growth of both cell line– and patient–derived B cell lymphoma and infiltration of human TAMs into the tumor. Treatment of rituximab with SE12C3 markedly inhibited B–cell lymphoma growth in HIS-MITRG mice. The inhibition of B–cell lymphoma growth depended on human macrophages and was attributable to the promotion of rituximab–mediated lymphoma cell phagocytosis by human macrophages. In addition, the treatment of rituximab with SE12C3 induced reprogramming of human TAMs towards the pro-inflammatory phenotype in the TME. Furthermore, we demonstrated that the treatment of rituximab with SE12C3 significantly inhibited diffuse large B–cell lymphoma patient–derived tumor growth in HIS–MITRG mice. Together, HIS–MITRG mice provide an excellent mouse model for in vivo preclinical evaluation of the anti-tumor effect of therapeutics targeting human TAMs in the TME, such as anti–human SIRPα antibodies.

2023-09-30 | GSE239693 | GEO

Preclinical evaluation of the efficacy of an antibody to human SIRPα for cancer immunotherapy in humanized mouse models.

Project description:Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment and are considered potential targets for cancer immunotherapy. To examine the antitumor effects of agents targeting human TAMs in vivo, we here established preclinical tumor xenograft models based on immunodeficient mice that express multiple human cytokines and have been reconstituted with a human immune system by transplantation of human CD34+ hematopoietic stem and progenitor cells (HIS-MITRG mice). HIS-MITRG mice supported the growth of both human cell line (Raji)- and patient-derived B cell lymphoma as well as the infiltration of human macrophages into their tumors. We examined the potential antitumor action of an antibody to human SIRPα (SE12C3) that inhibits the interaction of CD47 on tumor cells with SIRPα on human macrophages and thereby promotes Fcγ receptor-mediated phagocytosis of the former cells by the latter. Treatment with the combination of rituximab (antibody to human CD20) and SE12C3 inhibited Raji tumor growth in HIS-MITRG mice to a markedly greater extent than did rituximab monotherapy. This enhanced antitumor effect was dependent on human macrophages and attributable to enhanced rituximab-dependent phagocytosis of lymphoma cells by human macrophages. Treatment with rituximab and SE12C3 also induced reprogramming of human TAMs toward a proinflammatory phenotype. Furthermore, the combination treatment essentially prevented the growth of patient-derived diffuse large B cell lymphoma in HIS-MITRG mice. Our findings thus support the study of HIS-MITRG mice as a model for the preclinical evaluation in vivo of potential therapeutics, such as antibodies to human SIRPα, that target human TAMs.

| S-EPMC10757636 | biostudies-literature

Effects of a humanized CD47 antibody and SIRPα on triple negative breast carcinoma stem cells

Project description:Signal regulatory protein alpha (SIRPα, designated CD172a), also called SHPS-1 (SHP substrate 1) binds to CD47, a receptor for Thromobospondin-1 (TSP1). To block CD47-SIRP interaction, several CD47 blocking agents are in clinical trials. The purpose of this project is to explore the effects of SIRPFc signaling on bCSCs (breast cancer stem cells) derived from MDA-MB- 231 cells, when bCSCs were treated with either SIRPFc or CD47 blocking antibody CC90002 from Celgene Corporation.

2024-02-20 | GSE247052 | GEO

Effects of a humanized CD47 antibody and SIRPα on triple negative breast carcinoma stem cells

Project description:Effects of a humanized CD47 antibody and SIRPα on triple negative breast carcinoma stem cells

| PRJNA1036171 | ENA

SIRPα-CD47 axis regulates ILC2 effector function and alleviates airway hyperreactivity via modulating energy metabolism.

Project description:Type-2 innate lymphoid cells (ILC2) are part of a growing family of innate lymphocytes known for their crucial role in both the development and exacerbation of allergic asthma. In this study, we aim to elucidate the critical role of the suppressor molecule signal regulatory protein alpha (SIRPα), which interacts with CD47, in controlling ILC2-mediated airway hyperreactivity (AHR). Our data indicate that activated ILC2s upregulate the expression of SIRPα, and the interaction between SIRPα and CD47 effectively suppresses both ILC2 proliferation and effector function. To evaluate the efficacy of SIRPα in regulating ILC2-mediated AHR, we utilized SIRPα and CD47 deficient mice in a murine model of allergen-induced AHR. Our findings suggest that the absence of SIRPα leads to the overactivation of ILC2s. Conversely, engagement with SIRPα reduces ILC2 cytokine production and effectively regulates ILC2-dependent AHR. Furthermore, the SIRPα-CD47 axis modulates mitochondrial metabolism through the JAK/STAT and ERK/MAPK signaling pathways, thereby regulating NF-κB activity and the production of type two cytokines. Additionally, our studies on human cells have revealed that SIRPα is inducible and expressed on human ILC2s, and administration of a SIRPα agonist effectively suppresses the effector function and cytokine production of ILC2s. Moreover, administering human CD47-Fc to humanized ILC2 mice effectively alleviated AHR and lung inflammation. These findings highlight the promising therapeutic potential of targeting the SIRPα-CD47 axis in the treatment of ILC2-dependent allergic asthma.

2024-08-10 | GSE264061 | GEO

Tumor cell intrinsic type I interferon signaling dictates CD47-SIRPα blockade immunotherapy via metabolic reprograming [dataset 1]

Project description:Innate immune checkpoint has emerging as a highly potential target for cancer immunotherapy in recent years. The CD47-SIRPα axis is the best-studied innate checkpoint in cancer. However, the transcription profile of tumor cell duiring CD47-SIRPα blockade therapy remains unclear.

2024-06-04 | GSE235111 | GEO

Tumor cell intrinsic type I interferon signaling dictates CD47-SIRPα blockade immunotherapy via metabolic reprograming [dataset 2]

Project description:Type I interferons (IFN-Is) have been well recognized for their roles in immune cells in tumor immunotherapy. However, their direct effects on tumor cells are less understood. Oxidative phosphorylation (OXPHOS) is typically latent in tumor cells. However, whether OXPHOS can be targeted for immunotherapy remains unclear. Here, we found that tumor cell responsiveness to IFN-Is is essential for CD47-SIRPα blockade immunotherapy. Interestingly, IFN-Is directly reprogram tumor cell metabolism by activating OXPHOS for ATP production via ISG15. ATP extracellular release is also enhanced by IFN-Is via autophagy. Tumor cells with a genetic deficiency in OXPHOS or autophagy were resistant to CD47-SIRPα blockade. ATP released upon CD47-SIRPα blockade primes the anti-tumor T cell response via ATP-P2X7 receptor-mediated dendritic cell activation. Further combination with inhibitors of ATP-degrading ectoenzymes, CD39 and CD73, showed synergistic anti-tumor effects. Together, these data reveal the unrecognized mechanisms of IFN-Is on tumor cell metabolic reprograming in tumor immunotherapy and provide novel strategies harnessing this pathway for enhanced efficacy of CD47-SIRPα blockade.

2024-06-04 | GSE235112 | GEO

A first-in-class, humanized antibody targeting alternatively spliced tissue factor: preclinical evaluation in an orthotopic model of pancreatic ductal adenocarcinoma

Project description:A first-in-class, humanized antibody targeting alternatively spliced tissue factor: preclinical evaluation in an orthotopic model of pancreatic ductal adenocarcinoma

| PRJNA666690 | ENA

Transcript profiling of WT and SIRPα KO BMDMs post-M1 activation in the presence of mCD47.ex

Project description:To compare the inflammatory responses of WT and SIRPα KO macrophage, we performed a complete transcript profiling of WT and SIRPα-KO M1 macrophage using transcriptome sequencing as a discovery platform. SIRPα-KO mice and WT mice were kept under the same condition. BMDMs were produced from WT and SIRPα-KO mice followed by M1 polarization. RNA was then isolated from the same number of BMDMs.

2021-03-19 | GSE169177 | GEO

First-in-class humanized antibody against alternatively spliced tissue factor augments anti-metastatic efficacy of chemotherapy in a preclinical model of pancreatic ductal adenocarcinoma

Project description:Alternatively spliced tissue factor (asTF) promotes progression of pancreatic ductal adenocarcinoma (PDAC) by activating beta1-integrins on PDAC cell surfaces. hRabMab1, a first-in-class, humanized, inhibitory, anti-asTF antibody we recently developed, can suppress PDAC primary tumor growth as a single agent. Whether hRabMab1 has the potential to suppress metastases in PDAC is unknown. Study results. When administered alone, hRabMab1 achieved only marginal penetration of experimental tumor tissue; however, hRabMab1 was abundant in tumor tissue when co-administered with gem/PTX which resulted in a significant decrease in tumor cell proliferation; leukocyte infiltration; and neovascularization. Gem/PTX alone reduced primary tumor volume, but not metastatic spread; only the combination of hRabMab1 and gem/PTX significantly reduced metastatic spread. RNAseq analysis of primary tumors showed that the addition of hRabMab1 to gem/paclitaxel enhanced the downregulation of tubulin binding and microtubule motor activity. In the liver, hRabMab1 reduced liver metastasis as a single agent. Only the combination of hRabMab1 and gem/PTX eliminated tumor cell-induced leukocytosis. Conclusions. This study demonstrates that hRabMab1 may help suppress metastasis in PDAC.

2024-12-31 | GSE252286 | GEO

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