Requirement of RORα for Maintenance and Anti-Tumor Immunity of Liver-Resident Natural Killer Cells/ILC1s.

BACKGROUD AND AIMS Liver type 1 innate lymphoid cells (ILC1s), also known as liver-resident natural killer (NK) cells, comprise a high proportion of total hepatic ILCs. However, factors regulating their maintenance and function remain unclear. APPROACH AND RESULTS In this study, we found high expression of RORα in liver-resident NK (LrNK) cells/ILC1s. Mice with conditional ablation of Rora in LrNK cells/ILC1s and conventional NK (cNK) cells had decreased LrNK cells/ILC1s but normal numbers of cNK cells. RORα-deficient LrNK cells/ILC1s displayed increased apoptosis and significantly altered transcriptional profile. Using a murine model of colorectal cancer liver metastasis, we found that RORα conditional deficiency resulted in more aggressive liver tumor progression and impaired effector molecule expression in LrNK cells/ILC1s. Consequently, treatment with the RORα agonist efficiently limited liver metastases and promoted effector molecule expression of LrNK cells/ILC1s. CONCLUSION Together, our study unveils a previously undefined role of RORα in LrNK cell/ILC1 maintenance and function, providing insights into the harnessing of LrNK cell/ILC1 activity in the treatment of liver cancer.