Murine hypodense eosinophils induce tumour cell apoptosis by a granzyme B-dependent mechanism

Costain, Darren J; Guha, Ashim K.; Liwski, Robert; Lee, Timothy D.G.

doi:10.1007/pl00006690

Cited by 33 publications

(15 citation statements)

References 19 publications

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“…Future therapies could benefit from specifically targeting eosinophils [45,[56][57][58] in order to optimize tumor rejection. Indeed, induction of eosinophils does not appear to simply constitute a bystander phenomenon but seems to directly or indirectly mediate tumor control [59][60][61][62][63][64][65].…”

Section: Discussionmentioning

confidence: 99%

Blood Eosinophilia Is an on-Treatment Biomarker in Patients with Solid Tumors Undergoing Dendritic Cell Vaccination with Autologous Tumor-RNA

et al. 2020

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Background: The approvals of immune checkpoint inhibitors for several cancer types and the rapidly growing recognition that T cell-based immunotherapy significantly improves outcomes for cancer patients led to a re-emergence of cancer vaccines, including dendritic cell (DC)-based immunotherapy. Blood and tissue biomarkers to identify responders and long-term survivors and to optimize cost and cost-effectiveness of treatment are greatly needed. We wanted to investigate whether blood eosinophilia is a predictive biomarker for patients with solid tumors receiving vaccinations with DCs loaded with autologous tumor-RNA. Methods: In total, 67 patients with metastatic solid tumors, who we treated with autologous monocyte-derived DCs transfected with total tumor mRNA, were serially analyzed for eosinophil counts and survival over the course of up to 14 years. Eosinophilic counts were performed on peripheral blood smears. Results: Up to 87% of the patients treated with DC-based immunotherapy experienced at least once an eosinophilia of ≥ 5% after initiation of therapy; 61 % reached levels of ≥ 10% eosinophils, and 13% of patients showed eosinophil counts of 20% or above. While prevaccination eosinophil levels were not associated with survival, patients with blood eosinophilia at any point after initiation of DC-based immunotherapy showed a trend towards longer survival. There was a statistically significant difference for the patients with eosinophil counts of 20% or more (p = 0.03). In those patients, survival was prolonged to a median of 58 months (range 2–111 months), compared to a median of 20 months (range 0–119 months) in patients with lower eosinophil counts. In 12% of the patients, an immediate increase in eosinophil count of at least 10 percentage points could be detected after the first vaccine, which also appeared to correlate with survival (65 vs. 24 months; p = 0.06). Conclusion: Blood eosinophilia appears to be an early, on-therapy biomarker in patients with solid tumors undergoing vaccination with RNA-transfected DC, specifically autologous tumor mRNA-transfected DC vaccines, and it correlates with long-term patient outcome. Eosinophilia should be systematically investigated in future trials.

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Section: Discussionmentioning

confidence: 99%

Blood Eosinophilia Is an on-Treatment Biomarker in Patients with Solid Tumors Undergoing Dendritic Cell Vaccination with Autologous Tumor-RNA

et al. 2020

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“…67 Migration and fusion of BNC with trinucleate cells, together with displacement and/or death of the remaining uterine LE, give rise to multinucleated syncytial plaques that cover the caruncles by day 24. Eosinophils may participate in this process by inducing cell death in uterine LE via perforin, granzyme B, and/or Fas ligand 68 for close association between trophectoderm and endometrial stroma for actions of stromal-derived growth factors on uterine receptivity to implantation.…”

Section: Hypoxia Inducible Factor 2amentioning

confidence: 99%

Interferons and Uterine Receptivity

2009

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This article focuses on the potential roles of interferons (IFNs) in establishing uterine receptivity to implantation. A common feature of the peri-implantation period of pregnancy in most mammals is production of type I and/or type II IFNs by trophoblasts that induce and/or stimulate expression of an array of IFN-stimulate genes (ISGs). These effects range from pregnancy recognition signaling in ruminants through IFN tau to effects on cellular functions of the uterus and uterine vasculature. For actions of IFNs, progesterone (P4) is permissive to the expression of many effects and to the expression of ISGs that are induced directly by an IFN or induced by P4 and stimulated by an IFN in a temporal and/or cell-specific manner. Uterine receptivity to implantation is P4 dependent; however, implantation events are preceded by loss of expression of progesterone (PGR) and estrogen (ESR1) receptors by uterine epithelia. Therefore, P4 likely acts via PGR-positive stromal cells to induce expression of fibroblast growth factors-7 and -10 and/or hepatocyte growth factor (progestamedins) that then act via their respective receptors on uterine epithelia and trophectoderm to affect expression of ISGs. The permissive effects of P4 on the expression of ISGs and the effects of P4 to induce and IFNs to stimulate gene expression raise the question of whether uterine receptivity to implantation requires P4 and IFN to activate unique, but complementary, cell signaling pathways. Uterine receptivity to implantation, depending on species, involves changes in the expression of genes for the attachment of trophectoderm to the uterine lumenal epithelium (LE) and superficial glandular epithelium (sGE), modification of the phenotype of uterine stromal cells, the silencing of PGR and ESR1 genes, the suppression of genes for immune recognition, alterations in membrane permeability to enhance conceptus-maternal exchange of factors, increased vascularity of the endometrium, activation of genes for transport of nutrients into the uterine lumen, and enhanced signaling for pregnancy recognition. Differential expression of genes by uterine LE/sGE, mid- to deep-glandular epithelia (GE), and stromal cells in response to P4 and IFNs is likely to influence uterine receptivity to implantation in most mammals. Understanding the roles of IFNs in uterine receptivity for implantation is necessary to develop approaches to enhance reproductive health and fertility in humans and domestic animals.

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“…Cellular immunity involves memory of an earlier exposure to antigen, leading to an elevated eosinophil response which can occur in the absence of humoral immunity [49]. Eosinophil numbers increase significantly during allergic phenomena [50,51], in parasitic [52,53] and viral infestation [54,55], in chronic inflammation [56,57] and in some cancers [58]. Eosinophils possess antibacterial properties [59], and can also kill nematode larvae, either alone or in conjunction with other immune components such as antibody or complement [60,61].…”

Section: General Information About Eosinophilsmentioning

confidence: 99%

A Role for Eosinophils in Adaptive Humoral Immunity~!2009-06-15~!2009-09-02~!2009-12-31~!

Speirs¹,

Speirs²,

Ponzio³

2010

TOIJ

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This review describes eosinophils in the context of their conspicuous presence as part of the memory (i.e., anamnestic) immune response to antigen. We propose a role for eosinophils, along with Antigen Presenting Cells (APC), in the initiation of humoral immune responses to protein antigens by memory T Helper-2 (TH2) cells and memory B lymphocytes. Eosinophils have long been known as a component of the inflammatory response induced during prolonged or repeated exposure to diverse antigens. However, their precise contribution to secondary antibody responses remains to be fully clarified. These morphologically unique granulocytes possess a wide assortment of preformed cytokines, interleukins, chemokines and RNAses (collectively known as eokines), which can be rapidly released during an inflammatory response to foreign proteins. Their accumulation and release of diverse eokines during the inflammation that accompanies an anamnestic response suggests an immunoregulatory function for eosinophils. Based on published results, we propose that preformed eokines attract dendritic cells and other APC to the inflammatory site and contribute to their maturation and activation. In addition, eosinophil RNAses and other enzymes catabolize cellular products (e.g., dsRNA complexes) released by antigen-activated memory TH2 cells undergoing apoptosis. As shown for other antigeninduced responses, B memory cells could bind components of RNA and other molecules present in the inflammatory exudate via their cell surface Toll Like Receptors (TLR), contributing to activation, clonal expansion, and differentiation into antibody-producing plasma cells. Overall, we present a unifying hypothesis to account for the presence and immunomodulatory role of eosinophils in the humoral immune response.

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Murine hypodense eosinophils induce tumour cell apoptosis by a granzyme B-dependent mechanism

Abstract: These data are consistent with a hypothesis that murine HD eosinophils elicit tumoricidal activity via a granzyme B-dependent mechanism.

Cited by 33 publications

References 19 publications

Blood Eosinophilia Is an on-Treatment Biomarker in Patients with Solid Tumors Undergoing Dendritic Cell Vaccination with Autologous Tumor-RNA

Blood Eosinophilia Is an on-Treatment Biomarker in Patients with Solid Tumors Undergoing Dendritic Cell Vaccination with Autologous Tumor-RNA

Interferons and Uterine Receptivity

A Role for Eosinophils in Adaptive Humoral Immunity~!2009-06-15~!2009-09-02~!2009-12-31~!

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