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Generation of eosinophils with potent antitumor activity from human pluripotent stem cells

ABSTRACT: The efficient infiltration of immune cells into tumors is a prerequisite for effective cancer immunotherapy. Eosinophils have been demonstrated to be able to quickly infiltrate tumors and recruit other immune effector cells to enhance the effects of antitumor treatments, indicating that eosinophils might provide the key to more effective cancer immunotherapies. In this study, we established a stepwise differentiation approach for generating large numbers of functional EPX+ eosinophils from human pluripotent stem cells (hPSCs) at near-100% purity. These hPSC-derived cells not only displayed eosinophil-specific phenotypes and expressed cytotoxic granular proteins, but more importantly, could also kill tumor cells in vitro, quickly infiltrate solid tumors in vivo and significantly suppress tumor growth in colorectal carcinoma and ovarian cancer xenograft mouse models. Our study therefore opens new avenues for the development of eosinophil-based immunotherapies to treat cancer.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE148907 | GEO | 2021/07/21

REPOSITORIES: GEO

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Metastasis-entrained eosinophils enhance lymphocyte-mediated anti-tumor immunity

Project description:The recognition of the immune system as a key component of the tumor microenvironment (TME) led to promising therapeutics. Since such therapies benefit only subsets of patients, understanding the activities of immune cells in the TME is required. Eosinophils are an integral part of the TME especially in mucosal tumors. Nonetheless, their role in the TME and the environmental cues that direct their activities are largely unknown, especially in metastasis. We report that breast cancer-driven lung metastasis is characterized by resident and recruited eosinophils. Eosinophil recruitment to the metastatic lung was regulated by G protein coupled receptor signaling but independent of CCR3. Functionally, eosinophils promoted lymphocyte-mediated anti tumor immunity. Transcriptome and proteomic analyses identified the TME rather than intrinsic differences between eosinophil subsets as a key instructing factor directing anti tumorigenic eosinophil activities. Specifically, TNF-a/IFN-g-activated eosinophils facilitated CD4+ and CD8+ T cell infiltration and promoted anti-tumor immunity. Collectively, we identify a mechanism by which the TME entrains eosinophils to adopt anti-tumorigenic properties, which may lead to the development of eosinophil-targeted therapeutics.

2021-07-27 | PXD027596 | Pride

Eftimie2010 - immunity to melanoma

Project description:The paper describes a model of immunity to melanoma. Created by COPASI 4.25 (Build 207) This model is described in the article: Modeling anti-tumor Th1 and Th2 immunity in the rejection of melanoma Raluca Eftimie, Jonathan L. Bramson, David J.D. Earn Journal of Theoretical Biology 265 (2010) 467–480 Abstract: Recent experiments indicate that CD4+ Th2 cells can reject skin tumors in mice, while CD4+ Th1 cells cannot (Mattes et al., 2003; Zhang et al., 2009). These results are surprising because CD4+ Th1 cells are typically considered to be capable of tumor rejection. We used mathematical models to investigate this unexpected outcome. We found that neither CD4+ Th1 nor CD4+ Th2 cells could eliminate the cancer cells when acting alone, but that tumor elimination could be induced by recruitment of eosinophils by the Th2 cells. These recruited eosinophils had unexpected indirect effects on the decay rate of type 2 cytokines and the rate at which Th2 cells are inactivated through interactions with cancer cells. Strikingly, the presence of eosinophils impacted tumor growth more significantly than the release of tumor-suppressing cytokines such as IFN-g and TNF-a. Our simulations suggest that novel strategies to enhance eosinophil recruitment into skin tumors may improve cancer immunotherapies. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

2019-07-30 | BIOMD0000000768 | BioModels

Metastasis-entrained eosinophils enhance lymphocyte-1 mediated anti-tumor immunity

Project description:The recognition of the immune system as a key component of the tumor microenvironment (TME) led to promising therapeutics. Since such therapies benefit only subsets of patients, understanding the activities of immune cells in the TME is required. Eosinophils are an integral part of the TME especially in mucosal tumors.Nonetheless, their role in the TME and the environmental cues that direct their activities are largely unknown, especially in metastasis. We report that breast cancer-driven lung metastasis is characterized by resident and recruited eosinophils. Eosinophil recruitment to the metastatic lung was regulated by G protein coupled receptor signaling but independent of CCR3. Functionally, eosinophils promoted lymphocyte-mediated anti53 tumor immunity. Transcriptome and proteomic analyses identified the TME rather than intrinsic differences between eosinophil subsets as a key instructing factor directing anti tumorigenic eosinophil activities. Specifically, TNF-a/IFN-g-activated eosinophils facilitated CD4+ and CD8+ T cell infiltration and promoted anti-tumor immunity. Collectively, we identify a mechanism by which the TME entrains eosinophils to adopt anti-tumorigenic properties, which may lead to the development of eosinophil-targeted therapeutics.

2021-08-06 | GSE181491 | GEO

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2023-10-17 | GSE237749 | GEO

Time-course Activation of Human Peripheral Blood Eosinophils by Cytokines

Project description:Activated eosinophils contribute to airway dysfunction and tissue remodeling in asthma, and thus are considered an important factor in asthma pathology. We report here comparative proteomic and phosphoproteomic changes upon activation of eosinophils using eight cytokines individually and in selected cytokine combinations, in time-course reactions. Differential protein and phosphoprotein expressions were determined by mass spectrometry after 2-dimensional gel electrophoresis (2DGE) followed by protein identification by MS, and by label-free LC-MS/MS. We found that each cytokine-stimulation produced significantly different changes in the eosinophil proteome and phosphoproteome, with phosphoproteomic changes being more pronounced and having an earlier onset. Furthermore, we observed that IL-5, GM-CSF, and IL 3 showed the greatest change in protein expression and phosphorylation, and this expression differed markedly from those of the other five cytokines evaluated. Comprehensive univariate and multivariate statistical analyses were employed to evaluate the comparative results. We also monitored eosinophil activation using flow cytometry (FC) analysis of CD69 expression. In agreement with our proteomic studies, FC indicated that IL-5, GM-CSF, and IL-3 were more effective than the other five cytokines studied in stimulating a cell surface CD69 increase indicative of eosinophil activation. Moreover, selected combinations of cytokines revealed proteomic patterns with many proteins in common with single cytokine expression patterns but also showed a greater than additive effect of the two cytokines employed, indicating a more complex signaling pathway that was reflective of a more typical inflammatory pathology.

2017-12-19 | PXD004043 | Pride

Eosinophils exert direct and indirect anti-tumorigenic effects in the development of esophageal squamous cell carcinoma [4NQOinDBLgata]

Project description:Eosinophils are present in several solid tumors and have context-dependent function. The role of eosinophils in the development of esophageal squamous cell cancer (ESCC), 85% of esophageal cancers worldwide, is unknown. Mice were treated with 4-nitroquinolone-1-oxide (4-NQO) for 8 weeks followed by vehicle for 8 weeks to induce esophageal squamous pre-cancer. Eosinophil depletion using three mouse models resulted in exacerbated 4-NQO tumorigenesis. RNA-sequencing on the whole esophagus of WT and ?dblGATA mice was done in the pre-cancer model to understand how the presence of eosinophils affects the pre-cancer esophageal environment.

2023-12-01 | GSE233443 | GEO

Expression profiles of sorted murine lung Eosinophils following allergen challenge

Project description:The eosinophil transcriptome analysis indicated a robust transcription change in eosinophils following allergen challenge in the lung. Eosinophils were FACS-sorted from Saline or OVA challenged lung with high purity and then subjected to genome-wide RNA microarray

2014-05-19 | E-GEOD-57757 | biostudies-arrayexpress

Eosinophils exert direct and indirect anti-tumorigenic effects in the development of esophageal squamous cell carcinoma [eos]

Project description:Eosinophils are present in several solid tumors and have context-dependent function. The role of eosinophils in the development of esophageal squamous cell cancer (ESCC), 85% of esophageal cancers worldwide, is unknown. Mice were treated with 4-nitroquinolone-1-oxide (4-NQO) for 8 weeks followed by vehicle for 8 weeks to induce esophageal squamous pre-cancer. Eosinophil depletion using three mouse models resulted in exacerbated 4-NQO tumorigenesis. In order to study the transcriptional profiles of eosinophils specifically, we isolated eosinophils from esophageal tissue of WT mice which had been treated with 4-NQO in the pre-cancer model. Because eosinophils are not present in the esophagus normally, we isolated eosinophils from the colons of a random subset of the same mice. Additionally, we derived eosinophils from the bone marrow of a random subset of the same mice.

2023-12-01 | GSE233448 | GEO

Mouse resident lung eosinophils are dependent on IL-5

Project description:Purpose: we aimed to characterized eosinophils in the murine model of asthma Methods: Eosinophils were sorted from the lung of naïve and and HDM-induced asthma mice. There after RNA was extracted from the sorted eosinophils and subjected to RNAseq. Results:we demonstrated that resident lung eosinophils require IL-5 for their survival and that the expression of Siglec-F, is regulated by IL-5 . Conclusion: Our data suggest that the distinct eosinophil populations in the asthmatic lung represent a continuum of activation states rather than distinct eosinophil subsets.

2023-04-17 | GSE203225 | GEO

Transcriptional analysis of TREM-1+ and TREM-1- airway eosinophils during allergic inflammation

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