IL33 Stimulates Innate Lymphoid Cells to Recruit CD8⁺ T Cells to PDACs

In mammalian tissues, group 2 innate lymphoid cells (ILC2) secrete type 2 cytokines and mediate the inflammatory and immune responses to pathogens and commensal organisms. These immune cells have also been observed in cancers, but their potential role in tumor immunity has not been well established. Moral and colleagues discovered that ILC2s infiltrate human pancreatic ductal adenocarcinomas (PDAC) as well as tumors from autochthonous and orthotopic mouse models of PDAC. In mice, the expansion and function of these tumor ILC2s (TILC2) depended on the ILC2-activating cytokine IL33, and RNA expression of IL33 was correlated with improved survival in patients with PDAC. Further experiments revealed that IL33 promoted antitumor immune responses in mouse models of PDAC, likely by activating TILC2s such that they primed CD8⁺ T cells. This priming appeared to be indirect, and additional experimental evidence suggested that TILC2s expanded due to IL33 exposure produced the chemokine CCL5, recruiting CD103⁺ dendritic cells, thus triggering recruitment and priming of CD8⁺ T cells. Highlighting the potential therapeutic relevance of these findings, IL33-activated TILC2s expressed PD-1, and combined treatment with recombinant IL33 plus a PD-1 antibody disrupted inhibitory PD-1 signaling on TILC2s to substantially reduce tumor size and improve survival in a mouse model of PDAC. Moreover, PD-1⁺ TILC2s and PD-1⁺ T cells were detected in many human PDACs, and IL33 and PDCD1 (encoding PD-1) mRNA levels correlated strongly in human PDACs. Collectively, these results designate a clear role for TILC2s in antitumor immunity, with their stimulation by IL33 culminating in CD8⁺ T-cell priming, and demonstrate that TILC2s may participate in the antitumor response triggered by blockade of PD-1 signaling.

Moral JA, Leung J, Rojas LA, Ruan J, Zhao J, Sethna Z, et al. ILC2s amplify PD-1 blockade by activating tissue-specific cancer immunity. Nature 2020;579:130–5.

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