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. 2025 Jan 6;21(1):2444697. doi: 10.1080/21645515.2024.2444697

From PD-1/PD-L1 to tertiary lymphoid structures: Paving the way for precision immunotherapy in cholangiocarcinoma treatment

Fang-Ju Huang a,*, Ye-Ying Fang b,*, Jia-Ying Wen c, Jian-Jun Li d, Qian Lin a, Qin-Yan Su a, Yi-Yang Chen a, Lei Wang a, Jian-Jia Zeng a, Bang-Teng Chi a, Rong-Quan He e, Di-Yuan Qin f, Li-Hua Yang e,✉,#, Gang Chen a,✉,#
PMCID: PMC12934183  PMID: 39757910

ABSTRACT

Cholangiocarcinoma (CCA) is a highly malignant hepatobiliary tumor characterized by limited treatment options and poor prognosis. The recent rise of immunotherapy has significantly influenced research in this field. This study presents a bibliometric analysis of 416 articles retrieved from the WOSCC, Wan fang Data, CNKI and VIP databases, spanning contributions from 32 countries, 589 institutions and 3,200 authors. The analysis identified “PD-L1,” “PD-1” and “pembrolizumab” as central research foci, while “immune checkpoint inhibitors,” “tumor immune microenvironment,” “tertiary lymphoid structures” and “durvalumab” emerged as key areas of interest. These findings emphasize the pivotal role of immunotherapy in improving survival outcomes for CCA, and they highlight the significance of tertiary lymphoid structures within the tumor microenvironment as a promising target for future research. This study offers a strategic overview of the evolving landscape of CCA immunotherapy, providing valuable insights to guide future scientific endeavors in this domain.

KEYWORDS: Cholangiocarcinoma, immunotherapy, bibliometrics, immune checkpoint inhibitor, tertiary lymphoid structures

Introduction

Cholangiocarcinoma (CCA) is a highly heterogeneous malignancy originating from the glandular epithelium of the biliary system.1 It can be classified into three main subtypes based on anatomical location: intrahepatic cholangiocarcinoma (iCCA), perihilar cholangiocarcinoma (pCCA) and distal cholangiocarcinoma (dCCA). For patients eligible for surgery, surgical resection remains the primary treatment. However, despite surgical intervention, postoperative recurrence occurs in up to 50%～60% of cases, and the five-year survival rate is approximately 30%.Adjuvant chemotherapy after surgery has variable effects, reducing recurrence and metastasis risks in iCCA and pCCA but not in dCCA.2–4

The global incidence of CCA is on the rise; due to its often-asymptomatic nature, many cases are diagnosed at advanced stages, making surgical treatment no longer viable. CCA is highly aggressive and resistant to treatment, which contributes to its high mortality rate. Despite recent advancements in surgical techniques and targeted therapies, treatment outcomes and prognosis remain unsatisfactory.5

In recent years, cancer immunotherapy has achieved remarkable success and has become a cornerstone of treatment for many malignancies.6 Immunotherapies targeting programmed cell death protein 1 (PD-1) and its ligand, programmed cell death ligand-1 (PD-L1), have demonstrated therapeutic efficacy for various cancers. A global, multicentre study found that the PD-L1 inhibitor durvalumab improved overall survival(OS) and progression-free survival (PFS) in advanced CCA patients when combined with gemcitabine and cisplatin; hence, the authors advocated for its use as a first-line therapy.7

However, research on immunotherapy for CCA lags behind that for other malignancies due to the complexity and heterogeneity of the disease.8 To gain insight into the research hotspots and development trends of this field, as well as to provide scholars with new research directions to promote the development of immunotherapy, this study systematically analyzed the literature on immunotherapy for CCA using bibliometric methods. Although several reviews of immunotherapy for CCA already exist, this study provides new insights into the field thanks to its use of the latest data, comprehensive literature search, and in-depth metrology analysis. Current CCA immunotherapy research focuses on three main areas: 1) exploring novel immune checkpoint inhibitors (ICIs) to enhance therapeutic efficacy, 2) investigating the impact of the tumor microenvironment on immunotherapy and 3) studying the role of tertiary lymphoid structures (TLS) in CCA immunotherapy. As ectopic lymphoid organs, TLS play a crucial role in anti-tumoral immune responses.

Bibliometrics, as defined by Alan Pritchard in 1969, is an interdisciplinary science combining mathematics, statistics and philology. It plays a key role in uncovering the characteristics of scientific literature, examining research trends and evaluating the quality of academic work. Unlike traditional reviews, bibliometric analyses rely on scientific methods and tools to systematically investigate the literature, thus providing more comprehensive overviews of academic fields.9

Materials and methods

Data collection

Articles on CCA immunotherapy were retrieved from WOSCC, CNKI, Wan fang Data and VIP, covering the period from the inception of these databases to 18 August 2024. To avoid data bias, the literature search was completed in a single day. The search strategy employed the following formula: topic=(“cholangiocarcinoma” OR “cholangiocellular carcinoma”) AND topic=(“immunotherapy” OR “immunotherapies” OR “immunotherapeutic” OR “immunotherapeutics” OR “immune therapy” OR “immunomodulator” OR “PD-L1 inhibitors” OR “PD-1 inhibitors” OR “CTLA-4 inhibitors” OR “cellular immunotherapy” OR “immune checkpoint inhibitor” OR “nivolumab” OR “pembrolizumab” OR “lambrolizumab” OR “atezolizumab” OR “avelumab” OR “durvalumab” OR “ipilimumab” OR “pidilizumab” OR “cemiplimab” OR “camrelizumab” OR “sintilimab” OR “toripalimab” OR “tislelizumab” OR “cadonilimab” OR “zimberelimab” OR “slurrymab” OR “penpulimab” OR “envafolimab” OR “adebrelimab” OR “sugemalimab”). The relevant articles were manually screened to exclude theses, conference papers, reviews and unrelated literature. The articles in Chinese from CNKI, Wan fang Data and VIP were exported in NoteExpress format and imported into NoteExpress version 4.0.0; then duplicate records were removed, and the data was exported in RefWorks format. After format conversion, this data was merged with the WOSCC data. The record content of the exported WOSCC data included the full record and cited references. The merged data was replaced with synonyms.

Data analysis

In R (version 4.4.0), we ranked the number of citations by article, country and author, as well as the number of publications by institution, author and journal; this was done by loading the Bibliometrix package, importing the cleaned data and using the overview, source and author columns on the left side of the page and the run-the-analysis column on the right side. Furthermore, we conducted a visual analysis of global annual publication volumes, publication output and collaborations by country, institutional collaborations, author collaborations, co-citation counts of journals and the evolution of keywords and topics.

Bibliometrix is a comprehensive R package for bibliometric analysis and scientific visualization developed by Massimo Aria and Corrado Cuccurullo. It supports data import, transformation, analysis and visualization, meeting the needs of bibliometric research.10

Results

Literature retrieval

A total of 807 articles were retrieved from WOSCC; 198 were obtained from CNKI; 330 were gathered from Wan fang Data and 26 were sourced from VIP. After excluding degree theses, conference papers, reviews and irrelevant documents, 360 articles were retained from WOSCC; 30 were kept from CNKI; 39 were saved from Wan fang Data, and 5 were retained from VIP. After deduplication, 56 articles remained from CNKI, Wan fang Data and VIP, resulting in a final dataset of 416 articles for analysis (Figure 1).

Figure 1.

Figure 1.

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Literature search and screening flowchart.

Analysis of annual publication volume and article citations

Prior to 2018, the annual publication volume was stable, with fewer than 10 articles published per year. Since 2018, there has been a rapid increase in publications, with a peak of 84 articles in 2022 (Figure 2). The most cited article (28 citations) is “Identification of Four Immune Subtypes Characterized by Distinct Composition and Functions of Tumor Microenvironment in Intrahepatic Cholangiocarcinoma,” which was published in HEPATOLOGY (Table 1).

Figure 2.

Figure 2.

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Annual production.

Table 1.

Top 10 most cited articles.

  Document DOI Year Local Citations Global Citations
1 JOB S, 2020, HEPATOLOGY 10 .1002/hep.31092 2020 28 177
2 FONTUGNE J, 2017, ONCOTARGET 10 .18632/oncotarget.15602 2017 22 130
3 LIN JZ, 2020, HEPATOBIL SURG NUTR 10 .21037/hbsn-20–338 2020 22 94
4 SABBATINO F, 2016, CLIN CANCER RES 10 .1158/1078-0432.CCR-15-0715 2016 21 150
5 MARABELLE A, 2020, J CLIN ONCOL 10 .1200/JCO.19.02105 2020 19 1684
6 ZHOU GY, 2019, J HEPATOL 10 .1016/j.jhep.2019.05.026 2019 17 74
7 KLEIN O, 2020, JAMA ONCOL 10 .1001/jamaoncol.2020.2814 2020 15 144
8 KANG J, 2020, CANCER RES TREAT 10 .4143/crt.2019.493 2020 14 50
9 MA LC, 2021, J HEPATOL 10 .1016/j.jhep.2021.06.028 2021 10 126
10 SHI GM, 2023, SIGNAL TRANSDUCT TAR 10 .1038/s41392-023 -01,317-7 2023 10 38
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Countries and cooperation between countries

The study included publications from 32 countries, with China contributing the greatest number of articles (896 publications), followed by the US (292 publications) (Figure 3). Despite China’s larger volume of publications, papers authored by US-based scholars had a significantly higher average citation count (13.3 citations per article for China vs. 92.6 citations per article for the US) (Table 2). The collaboration network shows frequent partnerships between China, the US, Japan and Germany (Figure 4).

Figure 3.

Figure 3.

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Number of publications by country. The darker the color, the higher the number of publications.

Table 2.

Top 10 countries by total citations and average citations per article.

  Country citations Average Article Citations
1 USA 4352 92.60
2 CHINA 2638 13.30
3 JAPAN 590 24.60
4 KOREA 440 25.90
5 FRANCE 384 38.40
6 THAILAND 297 16.50
7 GERMANY 241 21.90
8 AUSTRALIA 198 39.60
9 CANADA 125 62.50
10 NETHERLANDS 98 49.00
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Figure 4.

Figure 4.

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Country collaboration network map. Each node represents a country, and the thickness of the lines indicates the strength of collaboration between countries.

Institutional and inter-institutional cooperation

A total of 589 institutions worldwide contributed to the literature on CCA immunotherapy. Fudan University published the highest number of articles (117 papers) (Table 3). Figure 5 presents the institutional collaboration network, which highlights the close collaboration between the Chinese Academy of Medical Sciences – Peking Union Medical College and Peking Union Medical College Hospital. Close cooperation was also documented between the National Cancer Institute and the National Institutes of Health in the US, as well as between Harvard University and Harvard Medical School. The same was true of Fudan University and the Chinese Academy of Sciences.

Table 3.

Top 10 affiliations with the most publications.

  Institution Articles
1 FUDAN UNIVERSITY 117
2 SUN YAT SEN UNIVERSITY 56
3 NIH NATIONAL CANCER INSTITUTE (NCI) 54
4 NATIONAL INSTITUTES OF HEALTH (NIH) - USA 53
5 CHINESE ACADEMY OF MEDICAL SCIENCES - PEKING UNION MEDICAL COLLEGE 47
6 NAVAL MEDICAL UNIVERSITY 43
7 ASSISTANCE PUBLIQUE HOPITAUX PARIS (APHP) 42
8 MAHIDOL UNIVERSITY 42
9 PEKING UNION MEDICAL COLLEGE HOSPITAL 33
10 PEKING UNION MEDICAL COLLEGE 31
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Figure 5.

Figure 5.

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Institution collaboration network map. Each node represents an institution, and the thickness of the lines reflects the strength of collaboration between institutions.

Authors, co-cited authors and author collaboration network

A total of 3,200 authors produced the sampled literature. The most prolific author was J. Zhou (16 papers) (Table 4), while the most cited author was X. Yang (56 citations) (Table 5). Core authors in this field include J. Zhou, X. Yang, Y.Y. Wang and J. Fan. Furthermore, Zhou and Fan exhibited the closest collaboration (Figure 6).

Table 4.

Top 10 most published authors.

  Authors Articles
1 ZHOU J 16
2 FAN J 14
3 YENCHITSOMANUS PT 11
4 WANG YY 10
5 YANG X 10
6 ZHANG N 10
7 GAO Q 9
8 JUNKING M 9
9 PANYA A 9
10 YANG XB 9
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Table 5.

Top 10 most cited authors.

  Author LocalCitations
1 YANG X 56
2 AZOULAY D 50
3 CHERQUI D 50
4 WANG YY 45
5 ZHOU J 45
6 FAN J 43
7 YANG XB 40
8 ZHAO HT 40
9 LONG JY 38
10 SANG XT 38
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Figure 6.

Figure 6.

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Author collaboration network map. Each node represents an author, and the thickness of the lines reflects the strength of collaboration between authors.

Journals and journal co-citation counts

The 416 publications on CCA immunotherapy were published in 205 journals. The top 10 journals by publication count are presented in Table 6. The Journal of Hepatology and Clinical Cancer Research were identified as the core journals in this field (Figure 7).

Table 6.

Top 10 journals by publication volume.

  Sources Articles
1 FRONTIERS IN IMMUNOLOGY 28
2 FRONTIERS IN ONCOLOGY 27
3 CANCER IMMUNOLOGY IMMUNOTHERAPY 11
4 JOURNAL OF HEPATOLOGY 11
5 JOURNAL FOR IMMUNOTHERAPY OF CANCER 10
6 CLINICAL CANCER RESEARCH 8
7 JOURNAL OF GASTROINTESTINAL ONCOLOGY 7
8 SCIENTIFIC REPORTS 7
9 BMC CANCER 6
10 FRONTIERS IN PHARMACOLOGY 6
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Figure 7.

Figure 7.

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Journal Co-citation network map. Each node representing a journal, with thicker lines indicating a higher number of co-citations between journals.

Keyword and topic analysis

The data was imported into the Bibliometrix package, and a visualization analysis of the authors’ keywords was conducted. This resulted in two views: the trend topics map and the thematic map. “PD-L1,” “PD-1” and “pembrolizumab” emerged as research hotspots in the field, while “immune checkpoint inhibitor,” “immune microenvironment,” “tertiary lymphoid structures” and “durvalumab” were prominent subjects (Figure 8a). In the thematic map, the Cartesian coordinate framework is divided into four quadrants, each defined by distinct centrality and density metrics. The first quadrant (motor themes) includes high-maturity core themes, such as “PD-L1,” “PD-1” and “pembrolizumab.” The second quadrant (niche themes) contains high-maturity isolated themes, such as “immune infiltration,” “gemcitabine,” “cellular immunotherapy” and “conversion therapy.” The third quadrant (emerging or declining themes) includes new or declining topics (e.g., “cancer immunotherapy”), while the fourth quadrant (basic themes) encompasses low-maturity foundational topics likely to become future research trends, such as “immune checkpoint inhibitor,” “immune microenvironment” and “tertiary lymphoid structures” (Figure 8b).

Figure 8.

Figure 8.

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(a) trend topics map. The size of the circles represents the frequency of keyword occurrence, and the horizontal lines indicate the duration of the keyword’s presence. Figure 8(b). Thematic map. The X-axis represents centrality; greater centrality indicates a theme’s higher importance and level of attention within the network. The Y-axis represents density; greater density reflects a theme’s stability and maturity in research.

Discussion

CCA exhibits a limited ability to stimulate the body’s immune system to mount an effective response. This characteristic may facilitate immune evasion, allowing the tumor to persist and metastasize.11 T cells play a crucial role in orchestrating defense mechanisms against cancer. The PD-1 receptor on T cells, together with its ligand PD-L1, helps prevent autoimmunity and promotes immune tolerance. However, in the cancerous environment, tumor cells express PD-L1, which suppresses T cell-mediated anti-tumoral immunity via its interaction with PD-1. The use of anti-PD-1/PD-L1 antibodies blocks this interaction, thereby relieving T cell inhibition and restoring the body’s anti-tumoral capabilities.12,13 Notably, research has shown that the PD-L1 induces T cells to become immunosuppressive regulatory T cells (Tregs). Consequently, inhibiting the PD-1/PD-L1 axis may enhance anti-tumoral immune responses within the tumor microenvironment by affecting various cell types.14

Molecules such as cytotoxic T lymphocyte antigen-4 (CTLA-4), PD-1 and PD-L1 are immune checkpoints that primarily regulate immune system activity. However, cancer cells exploit these checkpoints to evade immune surveillance. ICIs target molecules such as CTLA-4, PD-1 and PD-L1, thereby disinhibiting T cells and enabling them to more effectively recognize and attack tumor cells.15 Currently, there are three main categories of ICIs: 1) PD-1 inhibitors, such as pembrolizumab; 2) PD-L1 inhibitors, such as durvalumab; and 3) CTLA-4 inhibitors, such as ipilimumab.16

Pembrolizumab received FDA approval in May 2017 for treating DNA mismatch repair-deficient or microsatellite instability-high (MSI-H) unresectable or metastatic solid tumors, including hepatocellular carcinoma and CCA.17 In September 2022, durvalumab was approved by the FDA for first-line therapy in metastatic or advanced CCA.18 More recently, in 2024, pembrolizumab received FDA approval as a first-line treatment for advanced biliary tract cancer in combination with gemcitabine and cisplatin.11

The tumor immune microenvironment in CCA is a complex system comprising multiple cell types and cytokines, which significantly influences tumor growth, development and metastasis, as well as the effectiveness of treatments such as radiotherapy, chemotherapy and immune checkpoint therapy. A deeper understanding of CCA’s immune microenvironment is crucial for developing effective therapeutic strategies.19,20

Recent studies have demonstrated that tumor-infiltrating immune cells are highly concentrated in CCA tissue, suggesting that CCA is associated with an immune microenvironment conducive to the formation of TLS.21 TLS are ectopic lymphoid organs that develop in non-lymphoid tissue and consist mainly of T cells and B cells. Structurally, they resemble secondary lymphoid organs, such as lymph nodes and the spleen, with B cells concentrated in the center and surrounded by T cells. The presence of TLS in various pathological conditions, particularly in tumors, highlights their critical role in the body’s immune response. TLS provide an efficient site for immune cells to recognize, activate and attack tumor cells, thereby inhibiting tumor growth and metastasis. They also promote the generation of memory T and B cells, which can respond rapidly if the tumor reoccurs, offering long-lasting immune protection and potentially improving patient survival and quality of life. The presence and density of TLS in tumor tissue may serve as a predictor of the efficacy of immunotherapy and patient prognosis. Ongoing research into the composition and functionality of TLS, as well as its mechanism of action in anti-tumoral immune responses, is expected to pave the way for more targeted and effective immunotherapies.22–24

Since 2018, the annual publication volume related to CCA immunotherapy has seen a significant increase, reflecting growing interest in this area. The analysis of the citation rankings and co-citation networks revealed that the Journal of Hepatology and Clinical Cancer Research were the leading journals in the field. The Journal of Hepatology, which was founded in 1984, focuses on hepatology research and provides comprehensive information on liver disease treatment and management.25 Clinical Cancer Research, which was launched by the American Association for Cancer Research in 1995, is a premier journal for cancer research, including immunotherapy.26

Noteworthy studies have examined various aspects of cancer immunotherapy. For instance, a 2011 article demonstrated that the adoptive transfer of autologous anti-cancer T cells could result in the sustained regression of cancer in heavily pretreated melanoma patients.27 A 2007 study confirmed the safety and efficacy of bevacizumab for treating recurrent malignant gliomas, leading to its approval for recurrent glioblastoma.28 In 2003, a study on the expansion of Tregs in solid tumors provided insights into cancer immune-escape mechanisms, which laid the foundation for cancer immunotherapy breakthroughs.29

Professors Zhou and Yang have made significant contributions to this field. In a 2024 study, Zhou elucidated the clinicopathological and genetic characteristics of FGFR-altered intrahepatic cholangiocarcinoma, highlighting potential regional or ethnic variations in its incidence.30 In a 2021 study, Zhou demonstrated that the knockdown of germ cell-specific gene 2 protein (GSG2) inhibited CCA progression by modulating key processes, such as cell proliferation, apoptosis, cell cycle distribution and migration. This finding suggests that GSG2 could serve as a potential therapeutic target for CCA.31 Similarly, in a 2024 study, Yang found that MSI-H status correlated with elevated tumor mutation burden and positive PD-L1 expression in CCA. Moreover, in patients with advanced CCA undergoing PD-1 inhibitor immunotherapy, positive MSI-H and PD-L1 expression were associated with improved OS and PFS.32 In 2023, Yang also demonstrated that the quantitative assessment of the hypovascular component could aid in distinguishing combined hepatocellular-cholangiocarcinoma from hepatocellular carcinoma.33

The present study’s results indicate that China and the US are at the forefront of CCA research, with substantial collaboration between the two nations advancing immunotherapy development. Most inter-institutional partnerships occur between universities and their affiliated hospitals. However, strengthening the cooperation with nonaffiliated entities could promote scholarly exchange and the advancement of CCA immunotherapy.

In summary, this bibliometric analysis underscores the pivotal role of TLS in the immune microenvironment of CCA, suggesting that TLS are not only sites for immune cell aggregation but also potential biomarkers for predicting immunotherapy response and efficacy. Although the study of TLS in CCA is still an emerging field, its potential in guiding immunotherapy responses is evident. Future research should delve deeper into the mechanisms of TLS formation, their dynamic changes in CCA and their specific relationship with immunotherapy outcomes. The present review also noted that while ICIs have been approved for CCA treatment, the efficacy of single-agent ICIs remains limited, which highlights the promise of combination therapies. Exploring the combination of ICIs with other treatment modalities, such as chemotherapy, radiotherapy and molecular-targeted therapies, may improve therapeutic outcomes. Further studies are needed to refine immunotherapy regimens based on the molecular characteristics of CCA, with the help of advancements in genomics and proteomics. Precision medicine could benefit from gene sequencing in the attempt to identify specific mutations and expression patterns, thus guiding personalized ICI and targeted therapy choices. Furthermore, AI and machine learning could play a role in predicting immunotherapy responses and patient prognosis.

Beyond molecular therapies, immunotherapy also encompasses cell therapies and cancer vaccines. Cell therapy for CCA primarily enhances immune function to counteract tumor progression. A prominent approach is adoptive cell therapy(ACT), which utilizes the patient’s immune cells to fight the cancer. By isolating, expanding, and transplanting these cells, ACT boosts immune cell numbers and enables a more effective anti-tumoral response.34 Regarding cancer vaccines, their design is based on specific antigens present on the surface of cancer cells, namely tumor-associated antigens. Cancer vaccines stimulate the body’s immune system to produce specific responses against these antigens by introducing tumor-associated antigens. This response is mainly mediated by T cells, including CD4+ and CD8+ T cells. Dendritic cells play a key role in cancer vaccines. They are responsible for capturing, processing and presenting antigens to T cells, thereby triggering a strong anti-tumoral immune response.35

Recent studies have identified several molecular subtypes of CCA, with significant implications for personalized immunotherapy. For example, M.X. Deng’s team characterized two bile acid metabolism-related subtypes: C1 (bile acid metabolism-active) and C2 (bile acid metabolism-inactive). The C1 subtype was associated with a poor prognosis and an immunosuppressive microenvironment, making it less responsive to immunotherapy, whereas C2 could benefit more from this kind of treatment. This finding suggests that bile acid metabolism could serve as a marker for tailoring immunotherapy strategies.36 Additionally, Z.C. Wu found that CCA patients could be stratified into high- and low-risk subgroups based on oxidative stress pathways, with the high-risk subgroup exhibiting immune evasion mechanisms that may be targeted for novel immunotherapies.37

B. Gao highlighted two subtypes of CCA based on inflammation levels: the inflammation-high subtype (IHS) and the inflammation-low subtype (ILS). The IHS subtype was marked by an immunosuppressive microenvironment and frequent KRAS and TP53 mutations; it responded well to ICIs. The ILS subtype had greater tumor-killing cell infiltration, and it correlated with a better prognosis.38

Furthermore, Z.Q. Fan’s team classified CCA into specific molecular subtypes, among which the mesenchymal and immunosuppressive-C1 subtype showed significant immune evasion features. The over-expression of co-stimulator/co-inhibitor genes in this subtype may be an immune evasion mechanism caused by immune checkpoint over-expression. To this end, ICIs such as CTLA-4 and PDL1 can be used as treatment options. In contrast, the metabolic and proliferative-C2 subtype showed high immune cell infiltration but defective antigen presentation, which suggests that adjuvant chemotherapy or radiotherapy may enhance antigen recognition.39 Finally, X.W. Bao identified three proteomic subtypes: chronic inflammation, metabolism and chromatin remodeling. The first one had the poorest prognosis, which was driven by KMT2D mutations, APOE and C1QB upregulation. These are potential targets for personalized immunotherapy for iCCA.40

In recent advancements in the research on immunotherapy for CCA, several potential predictive factors and prognostic indicators have been identified, encompassing treatment duration, neutrophil-to-lymphocyte ratio, carcinoembryonic antigen levels, and the presence of bone metastasis, all of which can forecast patient survival following immunotherapy.41 Furthermore, CD8+ T cells have been established as an independent prognostic factor,42 while tumor mutation burden and MSI-H are recognized as independent risk predictors and favorable response indicators for immunotherapy in iCCA.43,44 Notably, the preoperative systemic immune-inflammation index (SII) has been validated as a prognostic marker for iCCA, with elevated SII levels correlating with poorer overall survival and early tumor recurrence, suggesting its potential future application in stratifying iCCA patients and guiding immunotherapy selection.45

Conclusion

CCA is an immunogenic tumor, and ICIs are a promising treatment option for it. The presence of TLS correlates with improved prognosis; therefore, studying TLS from a pharmacological perspective may enhance immunotherapy efficacy by reducing immunosuppression. Immunotherapy strategies tailored to the molecular subtypes and immune microenvironments of CCA patients hold the potential to improve treatment outcomes. The journey toward advancing immunotherapy for CCA is ongoing, and with continued research, it is expected to offer new hope for CCA patients.

Limitations

Bibliometric analysis typically relies on several indicators to assess the impact and quality of research, including citation counts, the number of publications and the frequency of specific keywords. However, these indicators have inherent limitations. For instance, citation counts can be influenced by various factors, such as the publication year and relative popularity of a research field. Also, some scholars and research institutions may prioritize quantity over quality by publishing lower-impact articles, which can skew citation metrics. Furthermore, differences in keyword indexing and terminological variations across authors may introduce bias in the frequency of keywords, potentially distorting the true prominence of specific research topics. Therefore, it is essential to continually refine bibliometric methods and indicators to enhance the accuracy, rigor and applicability of this kind of analysis.

Acknowledgments

We would like to express our gratitude to the “Guangxi Zhuang Autonomous Region Clinical Medicine Research Center for Molecular Pathology and Intelligent Pathology Precision Diagnosis” for providing computational pathology and clinical pathology technical support for this work.

Biography

Gang Chen, Professor, holds dual Ph.D. degrees, one in Oncology from Vrije Universiteit Brussel (VUB) in Belgium and another in Pathology from Guangxi Medical University. He serves as a supervisor for both doctoral and postdoctoral students, and is a clinical and molecular pathologist, as well as an experimental and computational pathologist. Professor Chen has studied abroad in Belgium, the Netherlands, Germany, France, and the United States. His research focuses on exploring various therapeutic molecular mechanisms of malignant tumors. He has published over 200 SCI articles.

Funding Statement

This work is supported by: Guangxi Zhuang Autonomous Region Health Commission Scientific Research Project (Z-A20240546, Z20201186).

Disclosure statement

No potential conflict of interest was reported by the author(s).

References

  • 1.Zhao R, Zhou J, Miao Z, Xiong X, Wei W, Li S, Guo R.. Efficacy and safety of lenvatinib plus durvalumab combined with hepatic arterial infusion chemotherapy for unresectable intrahepatic cholangiocarcinoma. Front Immunol. 2024;15:1397827. doi: 10.3389/fimmu.2024.1397827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Wang ML, Ke ZY, Yin S, Liu CH, Huang Q. The effect of adjuvant chemotherapy in resectable cholangiocarcinoma: a meta-analysis and systematic review. Hepatobiliary & pancreatic Dis Int. 2019;18(2):110–11. doi: 10.1016/j.hbpd.2018.11.001. [DOI] [PubMed] [Google Scholar]
  • 3.Nakanuma Y, Li Z, Sato Y, Sasaki M, Harada K, Kakuda Y, Sugino T. A pathological assessment of the microvasculature of biliary tract neoplasms referring to pre-existing blood vessels and vessel co-option. Cancers. 2024;16(22):3869. doi: 10.3390/cancers16223869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Chen B, Lu M, Chen Q, Zou E, Bo Z, Li J, Zhao R, Zhao J, Yu Z, Chen G, et al. Systematic profiling of mitochondria-related transcriptome in tumorigenesis, prognosis, and tumor immune microenvironment of intrahepatic cholangiocarcinoma: a multi-center cohort study. Front Genet. 2024;15:1430885. doi: 10.3389/fgene.2024.1430885. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Alvaro D, Gores GJ, Walicki J, Hassan C, Sapisochin G, Komuta M, Forner A, Valle JW, Laghi A, Ilyas SI, et al. EASL-ILCA clinical practice guidelines on the management of intrahepatic cholangiocarcinoma. J Hepatol. 2023;79(1):181–208. doi: 10.1016/j.jhep.2023.03.010. [DOI] [PubMed] [Google Scholar]
  • 6.Yuan M, Zhu Z, Mao W, Wang H, Qian H, Wu J, Guo X, Xu Q. Anlotinib combined with anti-PD-1 antibodies therapy in patients with advanced refractory solid tumors: a single-center, observational, prospective study. Front Oncol. 2021;11:683502. doi: 10.3389/fonc.2021.683502. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Rimini M, Fornaro L, Rizzato MD, Antonuzzo L, Rossari F, Satake T, Vandeputte H, Vivaldi C, Pressiani T, Lucchetti J, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer: a large real-life worldwide population. Eur J Cancer (Oxford, Engl: 1990). 2024;208:114199. doi: 10.1016/j.ejca.2024.114199. [DOI] [PubMed] [Google Scholar]
  • 8.Liang Z, Ge Y, Li J, Bai Y, Xiao Z, Yan R, An G, Zhang D. Targeting the PI3K/AKT/mTOR pathway offer a promising therapeutic strategy for cholangiocarcinoma patients with high doublecortin-like kinase 1 expression. J Cancer Res Clin Oncol. 2024;150(7):342. doi: 10.1007/s00432-024-05875-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Jia B, Chen J, Luan Y, Wang H, Wei Y, Hu Y. Artificial intelligence and atrial fibrillation: a bibliometric analysis from 2013 to 2023. Heliyon. 2024;10(15):e35067. doi: 10.1016/j.heliyon.2024.e35067. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Zhao J, Li M. Worldwide trends in prediabetes from 1985 to 2022: a bibliometric analysis using bibliometrix R-tool. Front Publ Health. 2023;11:1072521. doi: 10.3389/fpubh.2023.1072521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Tomlinson JL, Li B, Yang J, Loeuillard E, Stumpf HE, Kuipers H, Watkins R, Carlson DM, Willhite J, O’Brien DR, et al. Syngeneic murine models with distinct immune microenvironments represent subsets of human intrahepatic cholangiocarcinoma. J Hepatol. 2024;80(6):892–903. doi: 10.1016/j.jhep.2024.02.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Menon S, Shin S, Dy G. Advances in cancer immunotherapy in solid tumors. Cancers. 2016;8(12):106. doi: 10.3390/cancers8120106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Kwok G, Yau TC, Chiu JW, Tse E, Kwong YL. Pembrolizumab (Keytruda). Hum Vaccines & Immunotherapeutics. 2016;12(11):2777–2789. doi: 10.1080/21645515.2016.1199310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Wang S, Nie F, Yin Q, Tian H, Gong P, Ju J, Liu J, Yang P, Yang C. Periodontitis promotes tumor growth and immune evasion via PD-1/PD-L1. Cancer Immunol Immunother. 2024;74(1):22. doi: 10.1007/s00262-024-03865-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Sosa A, Lopez Cadena E, Simon Olive C, Karachaliou N, Rosell R. Clinical assessment of immune-related adverse events. Ther Adv Med Oncol. 2018;10:1758835918764628. doi: 10.1177/1758835918764628. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Zeng FL, Chen JF. Application of immune checkpoint inhibitors in the treatment of cholangiocarcinoma. Technol Cancer Res Treat. 2021;20:15330338211039952. doi: 10.1177/15330338211039952. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Zayac A, Almhanna K. Hepatobiliary cancers and immunotherapy: where are we now and where are we heading? Transl Gastroenterol Hepatol. 2020;5:8. doi: 10.21037/tgh.2019.09.07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Storandt MH, Jin Z, Mahipal A. Evaluating the therapeutic potential of durvalumab in adults with locally advanced or metastatic biliary tract cancer: evidence to date. Onco Targets Therap. 2024;17:383–394. doi: 10.2147/OTT.S391707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Liu Q, Zhu J, Huang Z, Zhang X, Yang J. Identification of novel cuproptosis-related genes mediating the prognosis and immune microenvironment in cholangiocarcinoma. Technol Cancer Res Treat. 2024;23:15330338241239139. doi: 10.1177/15330338241239139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Nishida N, Kudo M. Genetic/Epigenetic alteration and tumor immune microenvironment in intrahepatic cholangiocarcinoma: transforming the immune microenvironment with molecular-targeted agents. Liver Cancer. 2023;13(2):136–149. doi: 10.1159/000534443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Shang T, Jiang T, Lu T, Wang H, Cui X, Pan Y, Xu M, Pei M, Ding Z, Feng X, et al. Tertiary lymphoid structures predict the prognosis and immunotherapy response of cholangiocarcinoma. Front Immunol. 2023;14:1166497. doi: 10.3389/fimmu.2023.1166497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Sautès-Fridman C, Petitprez F, Calderaro J, Fridman WH. Tertiary lymphoid structures in the era of cancer immunotherapy. Nat Rev Cancer. 2019;19(6):307–325. doi: 10.1038/s41568-019-0144-6. [DOI] [PubMed] [Google Scholar]
  • 23.Schumacher TN, Thommen DS. Tertiary lymphoid structures in cancer. Sci (New Y, NY). 2022;375(6576):eabf9419. doi: 10.1126/science.abf9419. [DOI] [PubMed] [Google Scholar]
  • 24.Yu C, Xu J, Xu S, Tang L, Han Q, Sun Z. Research trends, hotspots and future directions of tertiary lymphoid structures in cancer: a comprehensive informatics analysis and visualization study. Discov Onc. 2024;15(1):665. doi: 10.1007/s12672-024-01556-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Jalan R. Emerging trends in hepatology: 30 years of the journal of hepatology and 50 years of EASL. J Hepatol. 2015;62(1):S1–S3. doi: 10.1016/j.jhep.2015.03.002. [DOI] [PubMed] [Google Scholar]
  • 26.Anderson KC, Potash J. Clinical cancer research: the 20th anniversary. Clin Cancer Res: An Off J Am Assoc For Cancer Res. 2015;21(1):3. doi: 10.1158/1078-0432.CCR-14-2455. [DOI] [PubMed] [Google Scholar]
  • 27.Rosenberg SA. CCR 20th anniversary commentary: autologous T cells-the ultimate personalized drug for the immunotherapy of human cancer. Clin Cancer Res: An Off J Am Assoc For Cancer Res. 2015;21(24):5409–5411. doi: 10.1158/1078-0432.CCR-14-3131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Mar N, Desjardins A, Vredenburgh JJ. CCR 20th anniversary commentary: bevacizumab in the treatment of glioblastoma--the progress and the limitations. Clin Cancer Res. 2015;21(19):4248–4250. doi: 10.1158/1078-0432.CCR-15-1381. [DOI] [PubMed] [Google Scholar]
  • 29.Wolf D, Wolf AM. CCR 20th anniversary commentary: from regulatory T cells to checkpoint monoclonal antibodies–immuno-oncology advances clinical cancer research. Clin Cancer Res: An Off J Am Assoc For Cancer Res. 2015;21(12):2657–2659. doi: 10.1158/1078-0432.CCR-14-2558. [DOI] [PubMed] [Google Scholar]
  • 30.Zhou J, Yu H, Zeng H, Shen Q, Wang X, & Xia Q. Intrahepatic cholangiocarcinoma with FGFR alterations: a series of Chinese cases with an emphasis on their clinicopathologic and genetic features. Digestive Liver Disease: Off J Italian Soc Gastroenterol Italian Assoc Study Liver. 2024;S1590-8658(24):00727–8. Advance online publication. doi: 10.1016/j.dld.2024.04.025. [DOI] [PubMed] [Google Scholar]
  • 31.Zhou J, Nie W, Yuan J, Zhang Z, Mi L, Wang C, Huang R. GSG2 knockdown suppresses cholangiocarcinoma progression by regulating cell proliferation, apoptosis and migration. Oncol Rep. 2021;45(6):91. doi: 10.3892/or.2021.8042. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Yang X, Lian B, Zhang N, Long J, Li Y, Xue J, Chen X, Wang Y, Wang Y, Xun Z, et al. Genomic characterization and immunotherapy for microsatellite instability-high in cholangiocarcinoma. BMC Med. 2024;22(1):42. doi: 10.1186/s12916-024-03257-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Yang X, Chang J, Li R, Qi Y, Zeng X, Wang W, Li H. Quantitative assessment of hypovascular component in arterial phase to help the discrimination of combined hepatocellular-cholangiocarcinoma and hepatocellular carcinoma. J Hepatocellular Carcinoma. 2023;10:113–122. doi: 10.2147/JHC.S390820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Zhao LM, Shi AD, Yang Y, Liu ZL, Hu XQ, Shu LZ, Tang YC, Zhang ZL. Advances in molecular and cell therapy for immunotherapy of cholangiocarcinoma. Front Oncol. 2023;13:1140103. doi: 10.3389/fonc.2023.1140103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Amhis N, Carignan J, Tai LH. Transforming pancreaticobiliary cancer treatment: exploring the frontiers of adoptive cell therapy and cancer vaccines molecular therapy. Oncology. 2024;32(3):200825. doi: 10.1016/j.omton.2024.200825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Deng M, Liu J, Zhang L, Lou Y, Qiu Y. Identification of molecular subtypes based on bile acid metabolism in cholangiocarcinoma. BMC Cancer. 2024;24(1):1313. doi: 10.1186/s12885-024-13081-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Wu Z. Transcriptomic analysis reveals oxidative stress-related signature and molecular subtypes in cholangio carcinoma. Mol Genet Genomics. 2024;299(1):86. doi: 10.1007/s00438-024-02170-1. [DOI] [PubMed] [Google Scholar]
  • 38.Gao B, Wang Y, Zhang X, Jiang H, Han F, Li C, Lu S. Identification and validation of inflammatory subtypes in intrahepatic cholangiocellular carcinoma. J Transl Med. 2024;22(1):730. doi: 10.1186/s12967-024-05529-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Fan Z, Zou X, Wang G, Liu Y, Jiang Y, Wang H, Zhang P, Wei F, Du X, Wang M, et al. A transcriptome based molecular classification scheme for cholangiocarcinoma and subtype-derived prognostic biomarker. Nat Commun. 2024;15(1):484. doi: 10.1038/s41467-024-44748-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Bao X, Li Q, Chen J, Chen D, Ye C, Dai X, Wang Y, Li X, Rong X, Cheng F, et al. Molecular subgroups of intrahepatic cholangiocarcinoma discovered by single-cell RNA sequencing–assisted multiomics analysis. Cancer Immunol Res. 2022;10(7):811–828. doi: 10.1158/2326-6066.CIR-21-1101. [DOI] [PubMed] [Google Scholar]
  • 41.Jin J, Mou H, Zhou Y, Zhang S. Nomogram for predicting survival post-immune therapy in cholangiocarcinoma based on inflammatory biomarkers. Cancer Control: J Moffitt Cancer Cent. 2024;31:10732748241305237. doi: 10.1177/10732748241305237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Chen L, Huang H, Huang Z, Chen J, Liu Y, Wu Y, Li A, Ge J, Fang Z, Xu B, et al. Prognostic values of tissue-resident CD8+T cells in human hepatocellular carcinoma and intrahepatic cholangiocarcinoma. World J Surg Onc. 2023;21(1):124. doi: 10.1186/s12957-023-03009-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Song JP, Liu XZ, Chen Q, Liu YF. High tumor mutation burden indicates a poor prognosis in patients with intrahepatic cholangiocarcinoma. World J Clin Cases. 2022;10(3):790–801. doi: 10.12998/wjcc.v10.i3.790. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Zeng T, Tao C, Yang G, Chen X, Yuan Z. Prognosis of advanced cholangiocarcinoma in the palliative care setting: a series of 201 cases. Altern Ther Health Med. 2022;28(2):24–31. [PubMed] [Google Scholar]
  • 45.Li H, Wang JJ, Zhang M, Ren B, Li JX, Xu L, Wu H. Prognostic significance of systemic immune-inflammation index in patients with intrahepatic cholangiocarcinoma undergoing hepatic resection. World J Gastrointestinal Oncol. 2020;12(4):467–482. doi: 10.4251/wjgo.v12.i4.467. [DOI] [PMC free article] [PubMed] [Google Scholar]

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