Tertiary lymphoid structures predict the prognosis and immunotherapy response of cholangiocarcinoma

Taiyu Shang; Tianyi Jiang; Tao Lu; Hui Wang; Xiaowen Cui; Yufei Pan; Mengyou Xu; Mengmiao Pei; Zhiwen Ding; Xiaofan Feng; Yunkai Lin; Xin Li; Yexiong Tan; Feiling Feng; Hui Dong; Hongyang Wang; Liwei Dong

doi:10.3389/fimmu.2023.1166497

Tertiary lymphoid structures predict the prognosis and immunotherapy response of cholangiocarcinoma

Front Immunol. 2023 May 10:14:1166497. doi: 10.3389/fimmu.2023.1166497. eCollection 2023.

Authors

Taiyu Shang^{1

2}, Tianyi Jiang¹, Tao Lu³, Hui Wang⁴, Xiaowen Cui¹, Yufei Pan¹, Mengyou Xu¹, Mengmiao Pei^{1

5}, Zhiwen Ding¹, Xiaofan Feng¹, Yunkai Lin¹, Xin Li⁴, Yexiong Tan¹, Feiling Feng⁵, Hui Dong³, Hongyang Wang^{1

2

6}, Liwei Dong^{1

6}

Affiliations

¹ National Center for Liver Cancer, Naval Medical University, Shanghai, China.
² School of Life Sciences, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China.
³ Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China.
⁴ Department of Hepatobiliary Diseases, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China.
⁵ Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China.
⁶ International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai, China.

Abstract

Introduction: Cholangiocarcinoma (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.

Methods: We 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.

Results: Different 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).

Conclusion: The 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.

Keywords: cholangiocarcinoma; immune checkpoint inhibitors; prognosis; tertiary lymphoid structures; tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bile Duct Neoplasms* / therapy
Bile Ducts, Intrahepatic / pathology
Cholangiocarcinoma* / genetics
Cholangiocarcinoma* / therapy
Humans
Immunotherapy
Prognosis
Tertiary Lymphoid Structures*
Tumor Microenvironment

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (32270814, 81830054, 81988101, 82172895, and 91859205), the National Key R&D Program of China (2022YFC2503704), the Shanghai Sailing Program (21YF1457900), the Clinical Research Plan of SHDC (SHDC2020CR2011A), Key project of Jiading District Health Construction Commission of Shanghai (No.2020-ZD-01), and the Basic Medical Research Foundation of the Naval Medical University (2021MS03 and 2021MS15).