Intra-Tumoral Secondary Follicle-like Tertiary Lymphoid Structures Are Associated with a Superior Prognosis of Overall Survival of Perihilar Cholangiocarcinoma

Abstract

Ectopic lymphoid structures termed tertiary lymphoid structures (TLSs) have an immunomodulatory function and positively affect prognosis in certain cancers. However, their clinical relevance and prognostic utility in perihilar cholangiocarcinoma (pCCA) are unknown. Therefore, determining the involvement and prognostic utility of TLSs in pCCA is the aim of this study. Ninety-three patients with surgically resected pCCA were included retrospectively. Hematoxylin and eosin and immunohistochemical staining identified and classified the TLSs, and multiplex immunofluorescence determined the TLS composition in the pCCA sample. The correlations between clinical features and TLSs were analyzed using either Fisher’s exact test or the Chi-squared test. Recurrence-free survival (RFS) and overall survival (OS) correlations with TLSs were analyzed using Cox regression and Kaplan–Meier analyses. We identified TLSs in 86% of patients with pCCA, including lymphoid aggregates (6.45%), primary (13.98%) and secondary follicles (65.59%). Patients with intra-tumoral secondary follicle-like TLSs (S-TLSs) had better OS (p = 0.003) and RFS (p = 0.0313). The multivariate analysis identified the presence of S-TLSs as a good independent prognostic indicator for OS but not for RFS. Interestingly, the presence of S-TLS only indicated better 5-year OS in 54 patients without lymph node metastasis (LNM−, p = 0.0232) but not in the 39 patients with lymph node metastasis (LNM+, p = 0.1244). Intra-tumoral S-TLSs predicted longer OS in patients with surgically resected pCCA, suggesting intra-tumoral S-TLSs’ contribution to effective antitumor immunity and that S-TLSs hold promise for diagnostic and therapeutic development in pCCA.

The enrichment of the gut microbiota Lachnoclostridium is associated with the presence of intratumoral tertiary lymphoid structures in hepatocellular carcinoma

“…With the study of the spatial distribution of immune cells within tumors, some aggregation patterns of immune cells have attracted attention due to their functional consistency in multiple tumor types and different individuals and potential clinical value, such as TLS ( 26 ). Since the back-to-back studies published in Nature successfully demonstrated that TLS affected the objective response rate of ICB in melanoma and was associated with good patient prognosis ( 10 , 27 ), similar conclusions have been obtained in most tumors ( 28 – 30 ). In particular, in a previous study by Mark Yarchoan, cabozantinib and nivolumab converted locally advanced HCC into a resectable disease, and significant enrichment of TLS was present in the tumor tissue of responders ( 31 ).…”

Unveiling the impact of tertiary lymphoid structures on immunotherapeutic responses of clear cell renal cell carcinoma

“…On the other hand, researches for other cancer types, such as colorectal and lung cancers, stressed the importance of having mature TLS in positive prognosis, which may add more pathological relevance to their function. 13,29,40,41 Since the intratumoral TLS that predict the better prognosis are predominantly mature TLS, investigating if TLS maturation could be the confounding reason for the difference in prognostic associations in ccRCC rather than the localization constitutes a possible goal for future research. Evidences suggest that E-TLS may be initiated from T cell factor 1 (TCF-1) -expressing stem-like T cells, which may interact with CD4 + CXCL13 + T helper cells and consequently attract B cells.…”

“…proposed that peritumoral TLS may not be directly associated with tumor but self‐antigens from inflamed tissues and should not be taken into account to analysis. On the other hand, researches for other cancer types, such as colorectal and lung cancers, stressed the importance of having mature TLS in positive prognosis, which may add more pathological relevance to their function 13,29,40,41 . Since the intratumoral TLS that predict the better prognosis are predominantly mature TLS, investigating if TLS maturation could be the confounding reason for the difference in prognostic associations in ccRCC rather than the localization constitutes a possible goal for future research.…”

“…25 Interestingly, patients with peritumoral TLS showed a prominently higher risk of reoccurrence and decreased clinical outcomes in breast and liver cancers. 26,40 Recently, Fridman et al proposed that peritumoral TLS may not be directly associated with tumor but self-antigens from inflamed tissues and should not be taken into account to analysis. On the other hand, researches for other cancer types, such as colorectal and lung cancers, stressed the importance of having mature TLS in positive prognosis, which may add more pathological relevance to their function.…”

An overview of extrahepatic cholangiocarcinoma: from here to where?

“…Notably, mucosal-associated invariant T cells possessing cytotoxicity and innateness were absent in the pCCA tumor microenvironment ( 87 ). Histologically, canonical tertiary lymphoid structures were associated with favorable survival in pCCA ( 88 ).…”