Introduction: Basophils are rare circulating granulocytes that participate in inflammatory processes such as allergic reactions and protective immunity against parasites. Inflammatory cells modulate tumor progression, but the role of basophils in cancer has been poorly studied.

Method: We used single cell RNA sequencing (scRNA-Seq), basophil depletion experiments, and cell co-culture systems, to explore the role and mode of action of basophils in mouse tumor models.

Results: scRNA-Seq showed that basophil numbers increase in the lung of mice with mammary tumors. However, basophil depletion enhanced metastatic seeding of breast cancer cells to the lung, which was associated with increased regulatory T cells (Tregs) numbers in different organs. Ex vivo cell assays indicated that basophils inhibited Treg function and induced Treg apoptosis via two mechanisms: (i) cleavage of the Treg IL-2RA by a basophil-secreted protease, Mcpt8; and (ii) engagement of the histamine type 1 receptor (HRH1) by basophil-derived histamine. Both mechanisms were conducive to enhanced activation of anti-tumoral CD8+ T cells. Disturbing the basophil-Treg crosstalk by loratadine, an antihistamine, promoted early tumor progression in mice. Accordingly, retrospective analysis of 11,000 patients with primary cancer from the Lausanne University Hospital showed a negative correlation between basophil numbers and risk of lung metastasis.

Conclusion: We have elucidated an anti-tumoral role of basophils, which is mediated via Treg suppression and CD8+ T cell activation. We further suggest that the use of antihistamines can abate the protective, anti-tumoral effect of basophils to facilitate early tumor growth.