IL-1 family members as regulators of lymphoid type-2 immunity in cancer

IL-1 family members, such as IL-1 and IL-33, are present in the tumor microenvironment and exert tumor-intrinsic and tumor-extrinsic functions with both pro- and anti-tumor effects. Among their immunoregulatory roles, both cytokines contribute to lymphoid type-2 immunity. IL-1 can indirectly promote CD4⁺ Th2 responses by inducing thymic stromal lymphopoietin production by tumor cells or cancer associated fibroblasts that conditions Th2-polarizing dendritic cells, whereas IL-33 is a potent direct activator of CD4⁺ Th2 and other type-2 immune cells, such as group 2 innate lymphoid cells (ILC2s). In a large majority of established human cancers, CD4⁺ Th2 cell responses correlate with tumor-promotion, whereas expansion of ILC2s can either suppress or promote tumor immunity in a more balanced way, leading to tumor progression or regression. Interestingly, the two prototypical Th2 cytokines IL-13 and IL-5 exert apparently pro- and anti-tumor opposing functions by recruitment of myeloid-derived cells and eosinophils, respectively. In addition, anti-tumor ILC2s under the influence of the tumor microenvironment may become dysfunctional, ultimately resulting in tumor-progression. Understanding the specific cancer context and considering the similarities as well as the distinctive features of the two lymphoid type-2 cell subsets is essential for developing effective immunotherapeutic strategies by targeting the IL-1 and IL-33 cytokines.