Tumoral Expression of IL-33 Inhibits Tumor Growth and Modifies the Tumor Microenvironment through CD8+ T and NK Cells

Abstract

Cancer immunotherapy has shown great promise as a new standard cancer therapeutic modality. However, the response rates are limited for current approach that depends on enhancing spontaneous antitumor immune responses. Therefore, increasing tumor immunogenicity by expressing appropriate cytokines should further improve the current immunotherapy. Interleukin-33 is a member of the IL-1 family of cytokines and is released by necrotic epithelial cells or activated innate immune cells and is thus considered a “danger” signal. The role of IL-33 in promoting type 2 immune responses and tissue inflammation has been well established. However, whether IL-33 drives antitumor immune responses is controversial. Our previous work established that IL-33 promoted the function of CD8+ T cells. Here, we showed that the expression of IL-33 in two types of cancer cells potently inhibited tumor growth and metastasis. Mechanistically, IL-33 increased numbers and IFNγ production by CD8+ T and NK cells in tumor tissues, thereby inducing a tumor microenvironment favoring tumor eradication. Importantly, IL-33 greatly increased tumor-antigen-specific CD8+ T cells. Furthermore, both NK and CD8+ T cells were required for the antitumor effect of IL-33. Moreover, depletion of regulatory T cells (Treg) worked synergistically with IL-33 expression for tumor elimination. Our studies established “alarmin” IL-33 as a promising new cytokine for tumor immunotherapy through promoting cancer-eradicating type 1 immune responses.

Intratumorally Establishing Type 2 Innate Lymphoid Cells Blocks Tumor Growth

“…The reason for the discrepancy between these results and ours is not known, but we suspect that the concentration of IL-33 present within tumors is a critical factor determining the tumor microenvironment. One study (13) reported (12,13,40,41), whereas lower doses of IL-33 seem to induce vigorous proliferation of ILC2s, as shown in the present study. Our results suggest that ILC2-governed responses may override the CD8 + immune response enhanced by IL-33 due to the dominance of a Th2 microenvironment.…”

“…Similar mechanisms, such as the IL-33-induced increase in IFN-g and perforin effector activities induced by NK cells and CD8 + T cells, act on eradicating IL-33-secreting tumors (13). The reason for the discrepancy between these results and ours is not known, but we suspect that the concentration of IL-33 present within tumors is a critical factor determining the tumor microenvironment.…”

“…Three studies have provided evidence supporting involvement of IL-33 in antitumor immune responses, that is, transgenic expression, injection as a vaccine adjuvant, or overexpression in tumor cells of IL-33, and increased antitumor immunity by promoting CTL responses to tumor cells (11)(12)(13). However, it is unknown whether type 2 innate lymphoid cells (ILC2s), which respond vigorously to IL-33, are involved in IL-33-mediated antitumor responses.…”

Wounds that heal and wounds that don’t − The role of the IL-33/ST2 pathway in tissue repair and tumorigenesis

“…IL-33 has also been shown to synergize with IL-12 to promote CD8 + T cell effector function [108]. In line with the ability of IL-33 to promote a CD8 + T cell response and the fact that CD8 + T cells mediate a vital role in the defence against cancer, over-expression of IL-33 potently inhibited tumour growth and metastasis in both B16 melanoma and 4T1 breast cancer models with both CD8+ T cell and NK cell numbers seen to be increased [109]. knockdown tumours as compared to the control tumours [29].…”

Exogenous interleukin‐33 targets myeloid‐derived suppressor cells and generates periphery‐induced Foxp3+ regulatory T cells in skin‐transplanted mice

“…21 As IL-33 may signal via ST2 on MDSCs to control their numbers, this cytokine could be modulating their suppressor activity as well. To corroborate this, we measured the relative expression of two characteristic MDSC genes involved in their modulatory function, iNOS and Arg1.…”