Harnessing Therapeutic IgE Antibodies to Re-educate Macrophages against Cancer

Pellizzari, Giulia; Bax, Heather J.; Josephs, Debra H.; Gotovina, Jelena; Jensen‐Jarolim, Erika; Spicer, James; Karagiannis, Sophia N.

doi:10.1016/j.molmed.2020.03.002

Cited by 20 publications

(23 citation statements)

References 80 publications

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“…Several studies have demonstrated that when designed to recognize tumour-associated antigens, IgE antibodies can activate immune cells, such as monocytes [8,15] and macrophages [21,22], to engender anti-tumour immunity by effector functions. Particularly, monocytes may play important roles in IgE-mediated anti-tumour efficacy.…”

Section: Introductionmentioning

confidence: 99%

IgE Activates Monocytes from Cancer Patients to Acquire a Pro-Inflammatory Phenotype

Nakamura

Souri

Osborn

et al. 2020

Cancers

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IgE contributes to host-protective functions in parasitic and bacterial infections, often by monocyte and macrophage recruitment. We previously reported that monocytes contribute to tumour antigen-specific IgE-mediated tumour growth restriction in rodent models. Here, we investigate the impact of IgE stimulation on monocyte response, cellular signalling, secretory and tumour killing functions. IgE cross-linking on human monocytes with polyclonal antibodies to mimic formation of immune complexes induced upregulation of co-stimulatory (CD40, CD80, CD86), and reduced expression of regulatory (CD163, CD206, MerTK) monocyte markers. Cross-linking and tumour antigen-specific IgE antibody-dependent cellular cytotoxicity (ADCC) of cancer cells by cancer patient-derived monocytes triggered release of pro-inflammatory mediators (TNFα, MCP-1, IL-10, CXCL-10, IL-1β, IL-6, IL-23). High intratumoural gene expression of these mediators was associated with favourable five-year overall survival in ovarian cancer. IgE cross-linking of trimeric FcεRI on monocytes stimulated the phosphorylation of intracellular protein kinases widely reported to be downstream of mast cell and basophil tetrameric FcεRI signalling. These included recently-identified FcεRI pathway kinases Fgr, STAT5, Yes and Lck, which we now associate with monocytes. Overall, anti-tumour IgE can potentiate pro-inflammatory signals, and prime tumour cell killing by human monocytes. These findings will inform the development of IgE monoclonal antibody therapies for cancer.

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Section: Introductionmentioning

confidence: 99%

IgE Activates Monocytes from Cancer Patients to Acquire a Pro-Inflammatory Phenotype

Nakamura

Souri

Osborn

et al. 2020

Cancers

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“…Finally, epidemiologic associations between atopies and protection against cancer development have been observed [ 62 , 63 ]. In that context, IgE has been reported to play a key role [ 63 ], possibly due to an IgE-driven macrophage rewiring [ 64 ]. However, besides this atopic protective effect, the fact that polynuclear macrophages arise from division defect, a major mechanism in tumorigenicity, suggests that some allergic inflammation and cancer mechanisms may overlap at the molecular levels.…”

Section: Discussionmentioning

confidence: 99%

GM-CSF and IL-33 Orchestrate Polynucleation and Polyploidy of Resident Murine Alveolar Macrophages in a Murine Model of Allergic Asthma

Quell

Dutta

Korkmaz

et al. 2020

IJMS

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Allergic asthma is a chronical pulmonary disease with high prevalence. It manifests as a maladaptive immune response to common airborne allergens and is characterized by airway hyperresponsiveness, eosinophilia, type 2 cytokine-associated inflammation, and mucus overproduction. Alveolar macrophages (AMs), although contributing to lung homeostasis and tolerance to allergens at steady state, have attracted less attention compared to professional antigen-presenting and adaptive immune cells in their contributions. Using an acute model of house dust mite-driven allergic asthma in mice, we showed that a fraction of resident tissue-associated AMs, while polarizing to the alternatively activated M2 phenotype, exhibited signs of polynucleation and polyploidy. Mechanistically, in vitro assays showed that only Granulocyte-Macrophage Colony Stimulating Factor and interleukins IL-13 and IL-33, but not IL-4 or IL-5, participate in the establishment of this phenotype, which resulted from division defects and not cell-cell fusion as shown by microscopy. Intriguingly, mRNA analysis of AMs isolated from allergic asthmatic lungs failed to show changes in the expression of genes involved in DNA damage control except for MafB. Altogether, our data support the idea that upon allergic inflammation, AMs undergo DNA damage-induced stresses, which may provide new unconventional therapeutical approaches to treat allergic asthma.

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“…This study also highlighted the need for repeated administration of IL-2 for T-cells to effect tumor eradication, even in the presence of PD-1 antibodies [ 20 ]. Hu-PDX models have also been utilized in the field of Allergo-Oncology, which is concerned with immune and allergic responses in cancer [ 58 ]. For example, in a hu-PDX model of ovarian cancer, IgE antibodies were used to prime tumor associated macrophages (TAMs) to elicit effector responses and restrict tumor proliferation [ 59 , 60 ].…”

Section: Murine Io Modelsmentioning

confidence: 99%

Modeling human tumor-immune environments in vivo for the preclinical assessment of immunotherapies

Bareham

Georgakopoulos

Matas-Céspedes

et al. 2021

Cancer Immunol Immunother

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Despite the significant contributions of immunocompetent mouse models to the development and assessment of cancer immunotherapies, they inadequately represent the genetic and biological complexity of corresponding human cancers. Immunocompromised mice reconstituted with a human immune system (HIS) and engrafted with patient-derived tumor xenografts are a promising novel preclinical model for the study of human tumor-immune interactions. Whilst overcoming limitations of immunocompetent models, HIS-tumor models often rely on reconstitution with allogeneic immune cells, making it difficult to distinguish between anti-tumor and alloantigen responses. Models that comprise of autologous human tumor and human immune cells provide a platform that is more representative of the patient immune-tumor interaction. However, limited access to autologous tissues, short experimental windows, and poor retention of tumor microenvironment and tumor infiltrating lymphocyte components are major challenges affecting the establishment and application of autologous models. This review outlines existing preclinical murine models for the study of immuno-oncology, and highlights innovations that can be applied to improve the feasibility and efficacy of autologous models.

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Harnessing Therapeutic IgE Antibodies to Re-educate Macrophages against Cancer

Cited by 20 publications

References 80 publications

IgE Activates Monocytes from Cancer Patients to Acquire a Pro-Inflammatory Phenotype

IgE Activates Monocytes from Cancer Patients to Acquire a Pro-Inflammatory Phenotype

GM-CSF and IL-33 Orchestrate Polynucleation and Polyploidy of Resident Murine Alveolar Macrophages in a Murine Model of Allergic Asthma

Modeling human tumor-immune environments in vivo for the preclinical assessment of immunotherapies

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