Eosinophilic Granulocytes and Damage-associated Molecular Pattern Molecules (DAMPs)

Abstract

The development of a tumor over many years typically leads to reciprocal alternations in the host and the tumor, enabling tumor growth paradoxically in the setting of substantial necrosis and inflammation. When evaluating a tumor, it is important to assess 3 elements: (1) the quantity and quality of tumor-associated leukocytes, (2) their state of activation, and (3) tumor microenvironment. Peripheral blood eosinophilia and tumor-associated tissue eosinophilia are frequently associated with some tumor types and also found after immunotherapy with IL-2, IL-4, granulocyte-macrophage colony-stimulating factor, and antibody to CTLA-4. Within several tumor types including gastrointestinal tumors, tumor-associated tissue eosinophilia is associated with a significantly better prognosis. The converse is true in other tumor types such as differentiated oral squamous cell carcinoma. On the basis of the emergent data, tumor-associated eosinophils have at least 2 dominant nonoverlapping activities: (1) destructive effector functions potentially limiting tumor growth as well as causing recruitment and activation of other leukocytes, (2) immunoregulative and remodeling activities which suppress immune response and promote tumor proliferation. The mechanism by which eosinophils in particular are recruited into tumor tissue is largely unknown. Candidates for causing eosinophil chemotaxis into tumor tissue are the released damage-associated molecular pattern molecules (DAMPs) including the nuclear protein high mobility group box 1. High mobility group box 1 is released upon necrotic cell death and secreted by many cells, particularly during periods of nutrient, hypoxic, or oxidant stress. This overview on eosinophil biology in the context of cancer and necrosis, introduces intriguing and novel strategies targeting eosinophils to enable more effective biologic therapy for cancer patients.

Tumor stress, cell death and the ensuing immune response

“…65 DAMPs can promote the specific recruitment of eosinophil or neutrophil granulocytes into tumors. [66][67][68] Indeed, HMGB1 release could promote the infiltration of eosinophils into tumor tissue (reviewed in 66 ). Peripheral blood eosinophilia and tumor-associated tissue eosinophilia are associated with objective responses during immunotherapy with interleukin-2, IL-4, granulocyte-macrophage colony-stimulating factor, and anti CTLA-4.…”

“…Peripheral blood eosinophilia and tumor-associated tissue eosinophilia are associated with objective responses during immunotherapy with interleukin-2, IL-4, granulocyte-macrophage colony-stimulating factor, and anti CTLA-4. 66,69 Treatment of tumor cells with irradiation or heat shock followed by membrane disruption was found to promote the release of IL-1a and the ICE-dependent recruitment of neutrophils towards dying tumor cells. In view of the fact that neutrophils could contribute to the elicitation of longterm antigen-specific CTL responses in melanoma models, 70 this result suggests that dying tumor cells can induce nonspecific inflammatory reaction that, in turn, may elicit a specific immune response.…”

Human mesenchymal stem cells respond to native but not oxidized damage associated molecular pattern molecules from necrotic (tumor) material

“…Released factors following necrotic cell death are also referred to as damage associated molecular patterns (DAMPs). DAMPs can critically impact the tumor microenvironment by enhancing angiogenesis or influencing the immune response [1,2]. Identified DAMPs -shared by almost all cell types -include S100, uric acid, ATP, hyaluronan, heat shock proteins, heparan, syndecan, versican, and high mobility group box 1 (HMGB1) [3].…”

Human Eosinophils Exert TNF-α and Granzyme A-Mediated Tumoricidal Activity toward Colon Carcinoma Cells

“…However, in many cancers, notably in carcinoma, eosinophils recruitment, commonly referred to as tumor-associated tissue eosinophilia (TATE), has been observed in some patients in tumor vicinity (3,4). Several epidemiological studies have attempted to correlate TATE and cancer prognosis or to study the relationships between allergy-related disorders and cancer development (5,6).…”