Abstract
Tumor-associated tertiary lymphoid structures (TLS) play a critical role in the progression of various tumors. However, the dynamics of lymphocyte recruitment during hepatocellular carcinoma (HCC) clinical progression have not been fully elucidated. In the present study, tissue microarrays and hematoxylin-eosin staining were used to evaluate the existence and degree of TLS in HCC patients. Nine immune biomarkers in intratumoral tissues were examined by immunohistochemical staining. A total of 462 patients were recruited for the study. Kaplan–Meier analysis showed that TLS was inversely correlated with the risk of early tumor recurrence (P=0.014), whereas no association was found between TLS and overall survival. Cox regression analysis identified TLS as an independent prognostic factor for early HCC recurrence (P=0.005). In addition, TLS was associated with increased intratumoral CD3+, CD8+, CD20+, and decreased infiltration of Foxp3+ and CD68+ cells. A lower density of PD1+, TIM3+, and LAG3+ were found in TLS+ cases. Sub-analysis revealed the prognostic value of TLS on early-stage HCC (BCLC 0-A, TNM stage I-II) and HCC with solitary nodule. The validation cohort verified the prognostic value of TLS in early-stage HCC patients. These results suggest that TLS-targeted immune-modulating therapies may be a potential strategy for effective immune-mediated tumor suppression.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the fourth leading cause of malignancy-related mortality worldwide [1]
The results of the present study showed that the existence and degree of tertiary lymphoid structures (TLS) maturation were associated with decreased risk of early HCC recurrence, but this was not linked to overall survival (OS) and late tumor relapse
It is noteworthy that the prognostic value of TLS was limited to BCLC stage 0-A HCC treated with surgical resection
Summary
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the fourth leading cause of malignancy-related mortality worldwide [1]. Studies on tumor-associated lymphocytes have suggested the formation of tertiary lymphoid structures (TLS) as a potential antitumor immune response [11,12,13]. Tertiary lymphoid structure describes ectopic lymphoid formations commonly observed in allograft rejection, autoimmune diseases and tumoral tissues [11, 14]. It exhibits all the characteristics of formation in normal lymph nodes [11]. Previous studies have associated the occurrence of TLS with decreased risk of recurrence and better overall survival (OS) in various solid tumors [15, 16]
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