RORc expressing immune cells support pro-tumorigenic functions of tertiary lymphoid structures

Abstract Tertiary lymphoid structures (TLSs) are formed in many cancer types and have been correlated with better prognosis and response to immunotherapy. In liver cancer, TLSs have been reported to be pro-tumorigenic as they harbor tumor progenitor cells and nurture their growth. The processes involved in TLS development and acquisition of pro- or anti-tumorigenic phenotype in cancer are largely unknown. RORc expressing immune cells have been previously implicated in TLS formation, however we find that they are not necessary for TLS neogenesis in the liver under chronic inflammation conditions. On the contrary, RORc expressing cells rather negatively regulate TLS formation, since in their absence TLSs form in excess. Importantly, in chronically inflamed livers lacking RORc expressing cells, pro-tumorigenic TLSs become anti-tumorigenic, resulting in reduction of tumor load. Comparing liver pro- and anti-tumorigenic TLSs by transcriptional, proteomic and immunohistochemical analyses, revealed an enrichment of exhausted CD8 cells that retained effector functions and had a progenitor-like proliferative phenotype in anti-tumorigenic TLSs. Similar observations were found when comparing pro- and anti-tumorigenic TLSs in human tissues. Thus, RORc expressing cells negatively regulate CD8 cell abundance, and facilitate the pro-tumorigenic functions of hepatic TLSs.