Peritumoral Tertiary Lymphoid Structures Correlate With Protective Immunity and Improved Prognosis in Patients With Hepatocellular Carcinoma

Abstract

The existence of intratumoral tertiary lymphoid structure (iTLS) has been reported to correlative with favorable clinical outcomes for patients with hepatocellular carcinoma (HCC). However, little is known about the role of peritumoral TLS (pTLS). This study aimed to investigate the prognostic role of pTLS either alone or jointly with iTLS and the potential association with local immune response in HCC. The formation and cellular composition of TLS was evaluated by hematoxylin & eosin and immunohistochemistry. Evaluation of tumor-infiltrating immune cells and formation of germinal center (GC) inside TLS was performed by immunohistochemistry. The gene expression profiles were analyzed by real-time PCR. In a total of 360 patients from two independent cohorts, the pTLS was identified in most, whereas iTLS could be observed in only approximately 30% of HCC specimens. Patients with high pTLS densities were associated with improved outcomes, those present with characteristic morphology of GC, particularly, showing an even better prognosis. The combination of pTLS and iTLS allowed the identification of patients with best prognosis. Tumors with high pTLS density showed significantly increased expression of Th1-, Th17- and immune suppression-related genes, as well as significantly higher infiltration of CD3+, CD8+ and CD20+ cells and lower infiltration of FOXP3+, CD68+ and PD1+ cells. Conclusively, we provide evidence that pTLS is associated with intratumoral immune infiltration, highlighting the dynamic interplay between pTLS and immune cells recruitment. High pTLS density links to a tumor microenvironment with an active immune reaction and improved patient survival and represents a promising prognostic biomarker for HCC.

Prognostic impact of tertiary lymphoid structures in breast cancer prognosis: a systematic review and meta-analysis

“…Notably, accurate detection of the number of TLSs is based on large pathological tissues, since extensive sampling can allow detection of more morphological structures. Studies have proven that intratumoral TLSs are an indicator of favorable prognosis in patients with pancreatic cancer [ 43 ], while peritumoral TLSs correlate with protective immunity and improved prognosis in patients with hepatocellular carcinoma [ 44 ], indicating the significance of TLSs localization in cancer patients. However, information on the specific histomorphological location is more dependent on extensive sampling; thus, larger pathological tissues imply a higher accuracy of morphological information and are of great importance for predicting the prognosis of patients.…”

Approaches to spatially resolving the tumour immune microenvironment of hepatocellular carcinoma

“…Interestingly in the same study, no correlation was found with TLSs and late reoccurrence. 57 These conflicting results may be explained by Li et al , 58 who found germinal centre formation within TLS of the peri-tumour improved prognostic outcome, which improved further if both intra-tumoural and peri-tumoural TLS were formed. It is only with techniques that allow for in situ analysis resulting in spatial data so that such structures and their significance can be elucidated.…”

Tertiary Lymphatic Structures in Primary Hepatic Carcinoma: Controversy Cannot Overshadow Hope

“…This can lead to worsening of the disease and an increase in tumor infiltration by CD4+ and CD8+ T cells and macrophages ( 71 ). TLS-related Tregs can also help tumor immune escape by inhibiting the endogenous immune response against the tumor simultaneously ( 57 , 81 , 82 ). In addition, compared with pTLS, although Tregs in iTLS are significantly increased, Tregs are only related to poor prognosis caused by pTLS ( 49 ).…”

“…However, the role of pTLS remains controversial. In a study by Li et al., pTLS density was related to good prognosis, that is, there was a positive correlation between high pTLS density and better overall survival (OS) and recurrence-free survival (RFS), and the survival rate of patients with a GC was higher than that of patients without a GC ( 81 ). They also observed that pTLS was significantly related to an increase in CD3+ T cells, CD8+ T cells, and CD20+ B cells in tumors, and also to a decrease in infiltration of Foxp3+, Tregs, and CD68+ macrophages ( 81 ).…”