Macrophages regulate PD-1 and CTLA-4 expression on ILC2s and their responsiveness in the tumor microenvironment.

Chronic inflammation can induce lymphocyte dysfunction, which is characterized by the expression of inhibitory immune checkpoints. For type 2 innate lymphoid cells (ILC2s), the acquisition of a state of hyporesponsiveness associated with PD-1 expression has been reported in severe allergic inflammation. However, the regulation of ILC2 reactivity in the context of cancer is less clear. The contribution of ILC2s to the antitumor immune response depends, indeed, on the type of tumor and the distinct cellular interplay within the microenvironment. Here, we show that ILC2s in malignant pleural effusions express the immune checkpoints PD-1 and CTLA-4. An in vitro model of the ILC2‒macrophage interaction demonstrated that this crosstalk is responsible for driving CTLA-4 expression and limiting ILC2 activation. Thus, by preventing ILC2 exhaustion, macrophages maintain ILC2 responsiveness to signals from the tissue. These results reveal that, unlike PD-1 expression, CTLA-4 expression on ILC2s is associated with the maintenance of a reactive state during chronic inflammation in the tumor microenvironment.