Tertiary lymphoid structures predict the prognosis and immunotherapy response of cholangiocarcinoma

Abstract

IntroductionCholangiocarcinoma (CCA) is a malignant tumor of the biliary epithelium with a poor prognosis. The lack of biomarkers to predict therapeutic response and prognosis is one of the major challenges for CCA treatment. Tertiary lymphoid structures (TLS) provide a local and pivotal microenvironment for tumor immune responses. The prognostic value and clinical relevance of TLS in CCA remain unclear. We aimed to explore the characteristics and clinical significance of TLS in CCA.MethodsWe investigated the prognostic value and clinical relevance of TLS in CCA using a surgery cohort containing 471 CCA patients (cohort 1) and an immunotherapy cohort containing 100 CCA patients (cohort 2). Hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining were used to evaluate the maturity of TLS. Multiplex IHC (mIHC) was employed to characterize the composition of TLS.ResultsDifferent maturity of TLS were observed in CCA tissue sections. Strong staining of the four-gene signature including PAX5, TCL1A, TNFRSF13C, and CD79A were found in TLS regions. A high density of intra-tumoral TLS (T-score high) were significantly correlated with longer overall survival (OS) both in CCA cohort 1 (p = 0.002) and cohort 2 (p = 0.01), whereas a high density of peri-tumoral TLS (P-score high) were associated with shorter OS in these two cohorts (p = 0.003 and p = 0.03, respectively).ConclusionThe established four-gene signature efficiently identified the TLS in CCA tissues. The abundance and spatial distribution of TLS were significantly correlated with the prognosis and immune checkpoint inhibitors (ICIs) immunotherapy response of CCA patients. The presence of intra-tumoral TLS are positive prognostic factors for CCA, which provide a theoretical basis for the future diagnosis and treatment of CCA.

The fibrosis-4 index is a prognostic factor for cholangiocarcinoma patients who received immunotherapy

“…Tertiary lymphoid structures can indicate the local immune infiltration status and their presence in various tumors has been associated with better immune responses (60,61). Thus, they hold significant potential for predicting immune reactions in cholangiocarcinoma (62) and warrant further exploration in subsequent studies.…”

Prognostic and predictive value of tertiary lymphoid structures in TURBT materials; Should it be seated in routine pathological examination and can it be used in deciding on the treatment method?

“…It was consistently associated with better patient survival, regardless of tumor stage, localization, microsatellite status, or treatment.Further studies have shown that TLS is associated with a favorable prognosis in most neoplasms including breast, pancreas, stomach, liver, lung,oral (Squamous cell carcinoma, SqCC), head and neck (SqCC), and oesophageal (SqCC) tumors regardless of the detection method [13,16,21].Moreover, there is also evidence that TLS has dual prognostic effects due to their spatial distribution (intratumoral/peritumoral), cellular composition, or possible effects of antitumor activity [22][23][24][25][26]. A recent study conducted on cholangiocarcinomas reported that intratumoral TLS is associated with a good prognosis and better e cacy of anti-PD-1 therapy, whereas a high abundance in the peritumoral localization is associated with lower immune response and poor prognosis [27]. A similar prognostic effect has been previously reported in the liver (Hepatocellular carcinoma) [24,26] and breast tumors [25].Conversely, there is evidence that peritumoral TLS density and maturity may be useful parameters to predict long-term survival in patients and response to anti-PD-1 antibody treatment [21].…”

Tertiary lymphoid structures in cancer: maturation and induction

“…Tumors exhibiting high-density peritumoral TLS exhibited significantly higher percentages of CD3 + , CD8 + and CD20 + cells, while showing decreased percentages of forkhead box P3 + , CD68 + and programmed cell death 1 (PD1 + ) cells in the TME ( 44 ). However, studies of other cancers such as intrahepatic cholangiocarcinoma, colorectal cancer, breast cancer, hepatocellular carcinoma, and cholangiocarcinoma have shown that intratumoral TLS was positively associated with better clinical outcomes, while peritumoral TLS was linked to a worse prognosis ( 45 – 48 ). These findings contradict the earlier conclusions.…”