Tertiary lymphoid structures (TLS) are associated with improved response in solid tumors treated with immune checkpoint blockade, but understanding of the prognostic and predictive value of TLS and the circumstances of their resolution is incomplete. Here we show that in hepatocellular carcinoma treated with neoadjuvant immunotherapy, high intratumoral TLS density at the time of surgery is associated with pathologic response and improved relapse-free survival. In areas of tumor regression, we identify a noncanonical involuted morphology of TLS marked by dispersion of the B cell follicle, persistence of a T cell zone enriched for T cell–mature dendritic cell interactions and increased expression of T cell memory markers. Collectively, these data suggest that TLS can serve as both a prognostic and predictive marker of response to immunotherapy in hepatocellular carcinoma and that late-stage TLS may support T cell memory formation after elimination of a viable tumor.

三级淋巴结构 （TLS） 与免疫检查点阻断治疗实体瘤反应的改善相关，但对 TLS 的预后和预测价值及其消退情况的理解尚不完整。在这里，我们表明，在接受新辅助免疫治疗的肝细胞癌中，手术时高瘤内 TLS 密度与病理反应和无复发生存期的提高相关。在肿瘤消退区域，我们确定了 TLS 的非经典退化形态，其标志是 B 细胞滤泡的分散、富含 T 细胞-成熟树突状细胞相互作用的 T 细胞区的持续存在以及 T 细胞记忆标志物表达的增加。总的来说，这些数据表明 TLS 可以作为肝细胞癌对免疫治疗反应的预后和预测标志物，并且晚期 TLS 可能支持消除活肿瘤后 T 细胞记忆的形成。