Tertiary lymphoid structures in hepatocellular carcinoma: Influence on immune cell profiles in tumors and on efficacy of adjuvant PD-1 inhibitor therapy after hepatectomy

Tertiary lymphoid structures (TLS) may promote immune responses to hepatocellular carcinoma (HCC) and thereby potentiate PD-1 inhibitor therapy. Whether the structures are associated with better prognosis of patients who receive adjuvant PD-1 inhibitors after curative hepatectomy is unclear. We analyzed the prevalence and maturity of TLS in tumors, the associations of such structures with survival after hepatectomy that was followed or not by adjuvant PD-1 inhibitor therapy, and the associations of the structures with the extent and profile of immune cells infiltrating tumors. Of 195 patients in prospective cohort who underwent hepatectomy followed by adjuvant PD-1 inhibitor therapy, the tumors in 109 (56%) contained TLS, and those patients showed significantly better recurrence-free (HR 0.69, 95%CI 0.44-0.98) and overall survival (HR 0.57, 95%CI 0.33-0.98) than those whose tumors lacked such structures. A nomogram taking into account the presence of such structures predicted recurrence at 1, 2 or 3 years with areas > 0.75 under the receiver operating characteristic curve. Tumors with TLS contained higher levels of CD3+ CD8+ PD-1+ T cells, PD-1+ natural killer T cells, B cells and granzyme B+ cells, but lower levels of regulatory T cells and macrophages, than tumors without such structures. The TLS may be associated with significantly longer recurrence-free and overall survival. This association may reflect synergy between TLS and adjuvant PD-1 inhibitor therapy in activating anti-tumor immune responses within tumors.