Tertiary lymphoid structures: Associated multiple immune cells and analysis their formation in hepatocellular carcinoma

Abstract

The prognostic value of immune cells in tertiary lymphoid structures (TLSs) remains unclear in hepatocellular carcinoma (HCC). Here, 59 of 145 patients had TLSs in training set, 48 of 120 patients had TLSs in testing set. Immunohistochemistry (IHC) were used to label CD3+ T cells, CD20+ B cells, CD8+ T cells, CD208+ dendritic cells, and CD21+ follicular dendritic cells in TLSs. High CD20+, CD208+, and CD8+ cell densities were favorable prognostic factors for overall survival (OS). High CD3+, CD20+, CD208+, and CD8+ cell densities were significantly associated with reduced early recurrence. TLSs were divided into three grades (A, B, and C) based on immune cell density. Patients with grade C or B had significantly improved OS. Patients with grade C had the lowest recurrence rate, followed by those with grade B, while patients with grade A had the highest recurrence rate. The stromal, immune, and ESTIMATE scores derived from the ESTIMATE package were significantly higher and tumor purity was significantly lower in patients with TLSs. Patients with TLSs had significantly higher relative numbers of memory B cells, plasma cells, CD8+ T cells, NK cells, and dendritic cells and lower relative numbers of Treg cells, macrophages, and M2 macrophages according to the CIBERSORT assessment. Bioinformatics analysis and experiments confirmed that KLRK1 and GZMA expression are associated TLSs formation and can predict TLSs existence. Grade B and grade C were favorable prognostic factors for OS and recurrence and could represent immuneactive tumors.

Deciphering the tumour immune microenvironment of hepatocellular carcinoma

“…Immunohistochemical analysis revealed that high CD20 + , CD208 + and CD8 + cell densities in HCC patients were favourable prognostic factors for overall survival. In contrast, high CD3 + , CD20 + , CD208 + and CD8 + cell densities were significantly associated with a reduction in early recurrence 116 . The differences in these results may be related to the study population, sample size, statistical methods, criteria for TLS identification, TLS heterogeneity and location.…”

“…In contrast, high CD3 + , CD20 + , CD208 + and CD8 + cell densities were significantly associated with a reduction in early recurrence. 116 The differences in these results may be related to the study population, sample size, statistical methods, criteria for TLS identification, TLS heterogeneity and location.…”

Characterization of lymphocyte‐rich hepatocellular carcinoma and the prognostic role of tertiary lymphoid structures

“…We performed a large-scale study of LR-HCC and C-HCC by analysing and comparing the clinicopathologic and molecular characteristics using proteomic analysis. Although there were previous reports highlighting the favourable prognostic effect of TLS in HCC, 12,[40][41][42] study cohorts were not histologically categorized into HCC subtypes including LR-HCC. In our findings, although LR-HCC showed a significant correlation to larger tumour size and higher ES grade compared to the C-HCC of similar disease stage, survival analysis revealed significantly better OS and RFS in LR-HCC.…”

Tertiary lymphoid structures in cancer: maturation and induction

“…These findings contradict the earlier conclusions. With an increased understanding of TLS, attention has been directed toward the maturity of TLS, revealing that mature TLS is linked to better cancer prognosis ( 49 ).…”