Basophils from allergy to cancer

Abstract

Human basophils, first identified over 140 years ago, account for just 0.5-1% of circulating leukocytes. While this scarcity long hampered basophil studies, innovations during the past 30 years, beginning with their isolation and more recently in the development of mouse models, have markedly advanced our understanding of these cells. Although dissimilarities between human and mouse basophils persist, the overall findings highlight the growing importance of these cells in health and disease. Indeed, studies continue to support basophils as key participants in IgE-mediated reactions, where they infiltrate inflammatory lesions, release pro-inflammatory mediators (histamine, leukotriene C₄: LTC₄) and regulatory cytokines (IL-4, IL-13) central to the pathogenesis of allergic diseases. Studies now report basophils infiltrating various human cancers where they play diverse roles, either promoting or hampering tumorigenesis. Likewise, this activity bears remarkable similarity to the mounting evidence that basophils facilitate wound healing. In fact, both activities appear linked to the capacity of basophils to secrete IL-4/IL-13, with these cytokines polarizing macrophages toward the M2 phenotype. Basophils also secrete several angiogenic factors (vascular endothelial growth factor: VEGF-A, amphiregulin) consistent with these activities. In this review, we feature these newfound properties with the goal of unraveling the increasing importance of basophils in these diverse pathobiological processes.

Keywords: allergy; angiogenesis; angiopoietins; basophil; cancer; cysteinyl leukotrienes; cytokines; vascular endothelial growth factors.

Figure 1

Schematic representation of the versatile role of basophils in the pathobiology of allergic disorders. Several immunological (i.e., allergens, superallergens, viral, bacterial and fungal proteins, cytokines) and non-immunological stimuli (e.g., pollutants, diesel exhaust particles) activate mucosal (i.e., lung and gut) and skin barriers to release different alarmins (i.e., TSLP, IL-33, IL-25) (130, 216, 217). Alarmins activate group 2 innate lymphoid cells (ILC2s) through the engagement of specific receptors (TSLPR, ST2, IL-25R, respectively) (218, 219) to release IL-5 and CCL11 that promote eosinophil infiltration into inflamed tissue (220, 221). Human and mouse basophils express the high-affinity receptor for IgE (FcεRI) (36, 37) and the receptors for IL-3 (IL-3Rα/CD123) (34, 44), GM-CSF (CD116) (45, 46), IL-33 (ST2/IL1RL1) (–50), IL-5 (CD125) (51) and a variety of chemokine receptors (, –60). The TSLP receptor (TSLPR/IL-7Rα) is expressed by mouse basophils (12, 34), but its presence on basophils from allergic and healthy donors remains controversial (, –16). TSLP activates mouse but not human basophils (12, 17). IL-3 plays a key role in the development, survival and activation of human and mouse basophils (17). IL-3 activates human and mouse basophils to release cytokines and chemokines (12, 17, 46, 222). IgE-FcεRI crosslinking by antigens, superallergens and functional anti-IgE autoantibodies activates basophils to release a wide spectrum of inflammatory and immunomodulatory factors (24, 70, 75, 76, 78, 79, 134, 211, 223). IL-33 activates human and mouse basophils to release several cytokines and chemokines (12). Activated human (, , –82) and mouse (12, 47, 80) basophils secrete large amounts of IL-4. Both human (, , , , –85) and mouse basophils (12, 47) also release IL-13. Human basophils secrete several angiogenic factors such as vascular endothelial growth factor-A (VEGF-A) (64). Basophil-derived IL-4 activates ILC2s to enhance the release of IL-5 and CCL11, leading to eosinophil infiltration (68). IL-4 promotes Th2 cell differentiation and enhances humoral immune responses (224). IL-4, together with IL-13, induces T follicular helper cells (Tfh) to promote IgE responses (225, 226). Basophil-derived IL-4 and IL-13 act on inflammatory monocytes inducing their differentiation into M2 macrophages (227). IL-4 and IL-13 activate fibroblasts to promote the production of chemokines (CCL5 and CCL11) (228) and collagen (229). IL-4 and IL-13 and vasoactive mediators (histamine, LTC₄, VEGF-A) act on blood endothelial cells (64, 230) to upregulate the expression of vascular cell adhesion molecule-1 (VCAM-1) (231), leading to enhanced trans-endothelial migration of eosinophils and basophils (186).

Figure 2

Theoretical representation of how basophils can promote tumor suppression. Basophils have been located in the immune infiltrate of several human (80, 102, 261, 262) and experimental tumors (80, 97, 102, 276). Vascular endothelial growth factors released by cancer cells and immune cells in tumor microenvironment (TME) (e.g., mast cells, macrophages) (, –123) can favor basophil infiltration in TME through the engagement of VEGFR2 on these cells (120). IL-3, produced by intratumoral lymphocytes, mast cells and cancer cells (17, 82, 281), is the most important growth and activating factor for human and mouse basophils, through the engagement of the IL-3 receptor (IL-3Rα/CD123) (17). CCL3/CCL4 secreted by intratumoral basophils induces CD8⁺ T cell recruitment in TME, promoting melanoma rejection in mice (270). IL-33, a pleiotropic cytokine produced by epithelial and tumor cells (282), plays a central role in tumorigenesis (282). IL-33 upregulates granzyme B mRNA and the surface expression of CD63, suggesting functional and phenotypic basophil activation. IL-33-activated mouse basophils induce melanoma cell death in vitro (67). Mouse (47, 86) and, under specific circumstances, human basophils (88, 89) release TNF-α. Human and mouse basophils release granzyme B (66, 67). Both TNF-α and granzyme B exert cytotoxic effects on tumor cells (68, 69). Activated signature (CD123, CCR3, CD63, CD203c gene expression) in tumor resident basophils is associated with improved outcome in ovarian cancer patients (248, 261). Topical exposure to a DNA-damaging carcinogen promotes tumor-protective IgE response through skin infiltrating basophils (276). Taken together, these results suggest that, in certain experimental and clinical conditions, basophils and their mediators may play an anti-tumorigenic role.

Figure 3

Theoretical representation of how basophils can promote tumor progression. Galectin-3 (Gal-3) is a lectin highly expressed by many types of cancer cells, frequently manifesting as a marker of poor prognosis with capacity to mediate immunosuppression within the tumor microenvironment (TME) (266). Recent in vitro studies show that Gal-3, expressed by the A549 adenocarcinoma cell line (or EC-Gal-3), has the capacity to activate basophils to secrete copious amounts of IL-4/IL-13 (16, 223). Both cytokines are known to promote M2-like macrophages, which are major players in the TME (, –265). IL-4-producing basophils have been identified in the TME of human pancreatic cancer, with mouse models indicating that this IL-4 promotes a Th2>Th1 response that is more conducive to tumorigenesis (80). Additionally, basophils are long known to secrete VEGF-A (64) that promotes angiogenesis. Other studies show that basophils can induce IL-6/IL-8 secretion from cell lines through a mechanism requiring cell-to-cell contact (283) (JTS, unpublished). This tumor cell-derived IL-6/IL-8 is implicated in playing a critical role in metastasis formation (284). Likewise, dendritic cells and monocytes activated by EC-Gal-3 are shown to produce high levels of TNF-α/IL-6 in vitro (285). Chronic production of these cytokines, when combined with M2 cell-derived IL-10/TGF-β, are implicated in promoting T-cell exhaustion by up-regulating checkpoint inhibitors (e.g., PD-1) that interact with tumor cell-associated markers (PD-L1) to suppress cytotoxic T cell activity (286). V-domain immunoglobulin suppressor of T-cell activation (VISTA) is another immune checkpoint receptor which plays a role in cancer progression (287, 288) and regulates allergen-specific Th2-mediated immune responses (289). Overall, it is proposed that the combined actions of these dysregulated innate immune responses synergize to promote tumorigenesis.