Eosinophils are major effectors of Th2-related pathologies, frequently found infiltrating several human
cancers. We recently showed that eosinophils play an essential role in anti-
tumor responses mediated by
immunotherapy with the '
alarmin' intereukin-33 (IL-33) in
melanoma mouse models. Here, we analyzed the mechanisms by which
IL-33 mediates
tumor infiltration and antitumor activities of eosinophils. We show that
IL-33 recruits eosinophils indirectly, via stimulation of
tumor cell-derived
chemokines, while it activates eosinophils directly, up-regulating CD69, the adhesion molecules
ICAM-1 and CD11b/CD18, and the degranulation marker CD63. In co-culture experiments with four different tumor cell lines, IL-33-activated eosinophils established large numbers of stable cell conjugates with target
tumor cells, with the polarization of eosinophil effector
proteins (ECP, EPX, and
granzyme-B) and CD11b/CD18 to immune synapses, resulting in efficient contact-dependent degranulation and
tumor cell killing. In
tumor-bearing mice,
IL-33 induced substantial accumulation of degranulating eosinophils within
tumor necrotic areas, indicating cytotoxic activity in vivo. Blocking of CD11b/CD18 signaling significantly reduced IL-33-activated eosinophils' binding and subsequent killing of
tumor cells, indicating a crucial role for this
integrin in triggering degranulation. Our findings provide novel mechanistic insights for eosinophil-mediated anti-tumoral function driven by
IL-33. Treatments enabling
tumor infiltration and proper activation of eosinophils may improve therapeutic response in
cancer patients.