A plausible explanation is that such a selective effect of ICOS signaling on irAE development or antitumor immunity depends on which cell types express ICOS in both organs with irAEs and tumor tissues, because ICOS-ICOSL interactions play a dual role in immune responses by acting on both effector T cells to promote their activation and Tregs to maintain their immunosuppressive activity (44). This evidence concerns the gene ICOS and neoplasm.