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

Abstract

In many types of cancer, presence of eosinophils in tumors correlate with an improved disease outcome. In line with this, activated eosinophils have been shown to reduce tumor growth in colorectal cancer (CRC). Interleukin (IL)-33 has recently emerged as a cytokine that is able to inhibit the development of tumors through eosinophils and other cells of the tumor microenvironment thereby positively influencing disease progress. Here, we asked whether eosinophils are involved in the effects of IL-33 on tumor growth in CRC. In models of CT26 cell engraftment and colitis-associated CRC, tumor growth was reduced after IL-33 treatment. The growth reduction was absent in eosinophil-deficient ΔdblGATA-1 mice but was restored by adoptive transfer of ex vivo-activated eosinophils indicating that the antitumor effect of IL-33 depends on the presence of eosinophils. In vitro, IL-33 increased the expression of markers of activation and homing in eosinophils, such as CD11b and Siglec-F, and the degranulation markers CD63 and CD107a. Increased expression of Siglec-F, CD11b and CD107a was also seen in vivo in eosinophils after IL-33 treatment. Viability and cytotoxic potential of eosinophils and their migration properties toward CCL24 were enhanced indicating direct effects of IL-33 on eosinophils. IL-33 treatment led to increased levels of IL-5 and CCL24 in tumors. Our data show that the presence of eosinophils is mandatory for IL-33-induced tumor reduction in models of CRC and that the mechanisms include eosinophil recruitment, activation and degranulation. Our findings also emphasize the potential use of IL-33 as an adjuvants in CRC immunotherapy.

The anti‐parasitic drug miltefosine suppresses activation of human eosinophils and ameliorates allergic inflammation in mice

“…We first performed Ca 2+ flux assays using mouse bone marrow‐derived eosinophils to test whether mouse eosinophils behave similar to human‐isolated eosinophils (Figure 4a,b). For that purpose, eosinophils were differentiated from bone marrow cells of BALB/c mice following an established protocol (Kienzl et al, 2020), which yields a pure population of cultured eosinophils as determined by a single population positive for mouse eosinophil markers CCR3 and Siglec‐F (Figure S4A). Microscopic analysis of cytospins of BMDEs shows a uniform population of cells exhibiting typical eosinophil staining and granule morphology (Figure S4B).…”

Fine-Tuning the Tumour Microenvironment: Current Perspectives on the Mechanisms of Tumour Immunosuppression

“…In an elegant model published by Demehri et al, transgenic K14 mice overexpressing dermal TSLP could successfully arrest breast and pancreatic tumour development, which was associated with an influx of GATA3 + Th2 cells to the primary tumour site [ 56 ]. Similarly, tumour growth was markedly reduced following IL-33 treatment, which was attributed to an increase in the migration and viability of cytotoxic eosinophils in a model for colorectal cancer [ 57 ]. In addition, IL-33 has been shown to drive anti-tumour CTL and NK cell activity that reduces melanoma tumour growth and metastasis [ 58 ].…”

Anti-Tumorigenic Activities of IL-33: A Mechanistic Insight

“…Injection (22) or tumor expression (57) of IL-33 in melanoma-bearing mice inhibited tumor growth and this effect was abolished upon eosinophil depletion by injections of anti-Siglec-F mAb. In models of transplantable and colitis-associated colorectal cancer, tumor growth reduction induced by IL-33 was abrogated in eosinophil-deficient DdblGATA-1 mice, but was restored by adoptive transfer of eosinophils activated with IL-33 ex vivo (52). Mechanistically, eosinophils can exert anti-tumor activity partly by promoting the recruitment of CD8 T cells (22,58).…”

“…In fact, eosinophils are an important source of chemokines (CCL5, CXCL9, CXCL10) that attract CD8 + T cells in TME (58) and can be up-regulated by administration of IL-33 (22). Moreover, eosinophils can exert direct tumor cytotoxicity (22,51,52). In a model of pulmonary melanoma metastasis, eosinophil depletion caused the inhibition of metastasis formation in mice receiving IL-33, without apparent involvement of cytotoxic CD8 + T cells, thus suggesting an active role of eosinophils in the lung (22).…”

“…In fact, IL-33 can directly activate human (59,60) and mouse (52, 61) eosinophils by up-regulating activation markers (i.e. CD69), adhesion molecules (i.e., ICAM-1 and CD11b/CD18), and the degranulation markers CD63 and CD107a, resulting in the killing of several tumor cell types (51,52,62,63). Once activated with IL-33, these granulocytes exert tumor cytotoxic functions through contact-dependent degranulation, involving polarization of eosinophilic effector proteins (eosinophil cationic protein, eosinophil peroxidase, and granzyme B) and convergence of lytic granules to the immunological synapses (51).…”