Macrophages regulate PD-1 and CTLA-4 expression on ILC2 and their responsivity in the tumor microenvironment

Chronic inflammation can induce lymphocyte dysfunction, characterized by the expression of inhibitory immune checkpoints. For type 2 innate lymphoid cells (ILC2), the acquisition of a state of hypo-responsiveness 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. ILC2 contribution to anti-tumor immune response depends, indeed, on the type of tumor and the distinct cellular interplays within the microenvironment. Here, we show that ILC2 in malignant pleural effusions express the immune checkpoints PD-1 and CTLA-4. An in vitro model of ILC2-macrophages interaction demonstrates that this crosstalk is responsible for driving CTLA-4 expression and limiting ILC2 activation. Thus, by preventing ILC2 exhaustion, macrophages maintain ILC2 responsivity to signals from the tissue. These results reveal that, differently from PD-1, CTLA-4 expression on ILC2 is associated with the maintenance of a reactive state during chronic inflammation in the tumor microenvironment. Overall design: RNA-sequencing was performed to compare gene expression between ILC2 sorted from co-culture with monocyte-derived-macrophages and ILC2 cultured alone.