Abstract
Group 2 innate lymphoid cells (ILC2s) are abundant in non-lymphoid tissues and increase following infectious and inflammatory insults. In solid tumors, however, ILC2s constitute a relatively small proportion of immune cells. Here, we show, using melanoma as a model, that while the IL-33/IL C2/eosinophil axis suppresses tumor growth, tumor-derived lactate attenuates the function and survival of ILC2s. Melanomas with reduced lactate production (LDHAlow) are growth delayed and typified by an increased number of ILC2s compared with control tumors. Upon IL-33 stimulation, ILC2s accompanied by eosinophils more effectively restrain the growth of LDHAlow tumors than control melanomas. Furthermore, database analysis reveals a negative correlation between the expression of LDHA and markers associated with ILC2s and the association of high expression of IL33 and an eosinophil marker SIGLEC8 with better overall survival in human cutaneous melanoma patients. This work demonstrates that the balance between the IL-33/ILC2/eosinophil axis and lactate production by tumor cells regulates melanoma growth.
Highlights
Innate lymphoid cells (ILCs) are lymphocytes that mirror the phenotypes and functions of T cells
Exclusion of Intratumoral ILC2s in B16 Tumors Given that ILC2s are numerous in certain tissues, we assessed the number of ILC2s in the skin and subcutaneous and mesenteric adipose tissues in naive and tumor-bearing mice using B16 melanomas as a model
After gating on live and LinÀCD45+ cells, the analysis revealed a roughly 3- and 4-fold increase in the number of Sca1+KLRG1+ ILC2s in the skin and subcutaneous adipose tissue from tumor-bearing mice compared with homeostatic cutaneous and subcutaneous ILC2 populations, respectively (Figures 1A, upper and center panels, and S1)
Summary
Innate lymphoid cells (ILCs) are lymphocytes that mirror the phenotypes and functions of T cells. ILC2s respond to the alarmin cytokines interleukin (IL)-33, IL-25, and thymic stromal lymphopoietin (TSLP, combined with IL-33) in addition to eicosanoids such as prostaglandin D2 and leukotriene D4, neuropeptides including neuromedin U, and sex hormones (Kabata et al, 2018). Following activation, they rapidly expand and produce cytokines such as IL-4, IL-5, IL-9, IL-13, and/or amphiregulin (Moro et al, 2010; Neill et al, 2010; Price et al, 2010; Kabata et al, 2013)
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