Is There a Role for Basophils in Cancer?

Abstract

Basophils were identified in human peripheral blood by Paul Ehrlich over 140 years ago. Human basophils represent <1% of peripheral blood leukocytes. During the last decades, basophils have been described also in mice, guinea pigs, rabbits, and monkeys. There are many similarities, but also several immunological differences between human and mouse basophils. There are currently several strains of mice with profound constitutive or inducible basophil deficiency useful to prove that these cells have specific roles in vivo. However, none of these mice are solely and completely devoid of all basophils. Therefore, the relevance of these findings to humans remains to be established. It has been known for some time that basophils have the propensity to migrate into the site of inflammation. Recent observations indicate that tissue resident basophils contribute to lung development and locally promote M2 polarization of macrophages. Moreover, there is increasing evidence that lung-resident basophils exhibit a specific phenotype, different from circulating basophils. Activated human and mouse basophils synthesize restricted and distinct profiles of cytokines. Human basophils produce several canonical (e.g., VEGFs, angiopoietin 1) and non-canonical (i.e., cysteinyl leukotriene C₄) angiogenic factors. Activated human and mouse basophils release extracellular DNA traps that may have multiple effects in cancer. Hyperresponsiveness of basophils has been demonstrated in patients with JAK2^V617F-positive polycythemia vera. Basophils are present in the immune landscape of human lung adenocarcinoma and pancreatic cancer and can promote inflammation-driven skin tumor growth. The few studies conducted thus far using different models of basophil-deficient mice have provided informative results on the roles of these cells in tumorigenesis. Much more remains to be discovered before we unravel the hitherto mysterious roles of basophils in human and experimental cancers.

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

Figure 1

Morphologic and ultrastructural differences between human basophils and mast cells. (A) Human peripheral blood basophil shows irregular blunt surface processes and a polylobed nucleus with condensed chromatin pattern. The cytoplasm contains large-membrane bound secretory granules filled with electron dense particles and/or finely granular material (11) X 21,500. (B) Isolated human lung mast cell has a narrow surface fold and single lobed nucleus with partially condensed chromatin pattern. The cytoplasm is filled with a large number of membrane-bound secretory granules that have an extremely variable ultrastructural pattern (16, 17). The cytoplasm also contains six non–membrane-bound spherical lipid bodies that are larger than secretory granules, are osmophilic and do not contain scrolls (16, 17) X 14,000. Photos kindly provided by Ann M. Dvorak and reproduced with permission from Marone et al. (18).

Figure 2

Proposed model of how basophils are recruited and activated in tumor draining lymph nodes (TDLNs) in the context of pancreatic cancer. It has been previously demonstrated (210) that cancer-associated fibroblasts (CAFs) can produce TSLP that engages TSLP receptor on dendritic cells (DCs). TSLP-conditioned DCs migrate into TDLNs were they prime CD4⁺ T cells for early IL-3 production. Monocytes, which are driven to differentiate toward a M2-type by activated CAFs, release the basophil chemoattractant CCL7/MCP3 (52). Basophils are recruited from afferent arterial blood into lymph nodes and are activated by IL-3 to express IL-4. Basophils are a major source of IL-4 contributing to both Th2 and M2 polarization. The percentage of basophils in TDLNs is an independent negative prognostic factor of survival after surgery of pancreatic cancer patients (91).