IL-33 Promotes CD11b/CD18-Mediated Adhesion of Eosinophils to Cancer Cells and Synapse-Polarized Degranulation Leading to Tumor Cell Killing

Abstract

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.

Tumor-Intrinsic or Drug-Induced Immunogenicity Dictates the Therapeutic Success of the PD1/PDL Axis Blockade

“…In addition to CD103 + DCs, intratumoral recruitment of eosinophils may contribute to tumor rejection through both direct cytotoxicity towards tumor cells and by secreting chemokines capable of attracting CD8 + T cells as recently reported [20,44,45]. The increase in tumor-infiltrating eosinophils in mice exposed to CTX/anti-PDL1/2 correlates with intratumoral expression of IL-33 which can both recruit and activate these cells [46]. Importantly, eosinophils are emerging as relevant immune biomarkers for response to ICIs in cancer patients, correlating with better clinical outcome [47].…”

Blood Eosinophilia Is an on-Treatment Biomarker in Patients with Solid Tumors Undergoing Dendritic Cell Vaccination with Autologous Tumor-RNA

“…Studies have suggested eosinophils to be part of an early inflammatory reaction at the site of tumorigenesis [27]. Eosinophils are not only a source of numerous cytokines and growth factors, but they also display both proinflammatory and anti-inflammatory activities, as well as immunoregulatory ones, which are most likely regulated by a complex network determined by surface molecules, extracellular components, and cell-cell interactions [28][29][30][31][32][33]. The role of eosinophils in allergic diseases led to several studies of the association between allergic conditions and cancer incidence [34,35].…”

IL-33 reduces tumor growth in models of colorectal cancer with the help of eosinophils

“…We, therefore, performed in vitro experiments by co-incubating eosinophils with CT26 cells and showed IL-33 dependent cytotoxic properties of eosinophils, corroborating data from studies in human and murine CRC and melanoma. 7,10,13,25 That lymphocytes may not be needed for the effects of eosinophils on cancer growth has been previously reported in different models of heterotopically engrafted solid tumors, 51 as well as in colitis-associated CRC models and Apc min/+ mice, which develop intestinal tumors spontaneously. 7 In our AOM +DSS-induced CRC model we detected IL-33-induced TATE, which was accompanied by reduced tumor growth, but we failed to see changes in the other leukocytes measured.…”

“…The other half of the cells was kept in normal IL-5-supplemented culture medium (IL-5 Eos) and served as a control. In vitro, incubation with IL-33 increased the expression of markers for activation and homing such as CD11b 13,39 and Siglec-F, 40 and markers of degranulation, such as CD63 13,41 and CD107a, 42 in eosinophils (Figure 2a).…”

“…12 A newly emerged cytokine that is able to influence tumor development via eosinophil activation is interleukin (IL)-33. 13 Although thought to be mostly pro-tumorigenic in many types of cancer [14][15][16] including CRC, [17][18][19][20][21][22][23][24] IL-33 was recently shown to reduce tumor growth in skin cancer and interestingly also in CRC models. [25][26][27] IL-33 is a member of the IL-1 family and normally released from damaged epithelial and endothelial barrier cells acting as an alarmin.…”