Tumor immune microenvironment and the current immunotherapy of cholangiocarcinoma (Review)

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Abstract

Cholangiocarcinoma (CCA) is a highly heterogeneous malignancy originating from the epithelial system of the bile ducts, and its incidence in recent years is steadily increasing. The immune microenvironment of CCA is characterized by diversity and complexity, with a substantial presence of cancer-associated fibroblasts and immune cell infiltration, which plays a key role in regulating the distinctive biological behavior of cholangiocarcinoma, including tumor growth, angiogenesis, lymphangiogenesis, invasion and metastasis. Despite the notable success of immunotherapy in the treatment of solid tumors in recent years, patients with CCA have responded poorly to immune checkpoint inhibitor therapy. The interaction of tumor cells with cellular components of the immune microenvironment can regulate the activity and function of immune cells and form an immunosuppressive microenvironment, which may cause ineffective immunotherapy. Therefore, the components of the tumor immune microenvironment appear to be novel targets for immune therapies. Combination therapy focusing on immune checkpoint inhibitors is a promising and valuable first-line or translational treatment approach for intractable biliary tract malignancies. The present review discusses the compositional characteristics and regulatory factors of the CCA immune microenvironment and the possible immune escape mechanisms. In addition, a summary of the advances in immunotherapy for CCA is also provided. It is hoped that the present review may function as a valuable reference for the development of novel immunotherapeutic strategies for CCA.

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Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

Dung Le, Jennifer N. Durham, Kellie N Smith … (2017)

The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers' tissue of origin.

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Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial

Anthony B El-Khoueiry, Bruno Sangro, Thomas CC Yau … (2017)

For patients with advanced hepatocellular carcinoma, sorafenib is the only approved drug worldwide, and outcomes remain poor. We aimed to assess the safety and efficacy of nivolumab, a programmed cell death protein-1 (PD-1) immune checkpoint inhibitor, in patients with advanced hepatocellular carcinoma with or without chronic viral hepatitis. We did a phase 1/2, open-label, non-comparative, dose escalation and expansion trial (CheckMate 040) of nivolumab in adults (≥18 years) with histologically confirmed advanced hepatocellular carcinoma with or without hepatitis C or B (HCV or HBV) infection. Previous sorafenib treatment was allowed. A dose-escalation phase was conducted at seven hospitals or academic centres in four countries or territories (USA, Spain, Hong Kong, and Singapore) and a dose-expansion phase was conducted at an additional 39 sites in 11 countries (Canada, UK, Germany, Italy, Japan, South Korea, Taiwan). At screening, eligible patients had Child-Pugh scores of 7 or less (Child-Pugh A or B7) for the dose-escalation phase and 6 or less (Child-Pugh A) for the dose-expansion phase, and an Eastern Cooperative Oncology Group performance status of 1 or less. Patients with HBV infection had to be receiving effective antiviral therapy (viral load <100 IU/mL); antiviral therapy was not required for patients with HCV infection. We excluded patients previously treated with an agent targeting T-cell costimulation or checkpoint pathways. Patients received intravenous nivolumab 0·1–10 mg/kg every 2 weeks in the dose-escalation phase (3+3 design). Nivolumab 3 mg/kg was given every 2 weeks in the dose-expansion phase to patients in four cohorts: sorafenib untreated or intolerant without viral hepatitis, sorafenib progressor without viral hepatitis, HCV infected, and HBV infected. Primary endpoints were safety and tolerability for the escalation phase and objective response rate (Response Evaluation Criteria In Solid Tumors version 1.1) for the expansion phase. This study is registered with ClinicalTrials.gov , number NCT01658878 . Between Nov 26, 2012, and Aug 8, 2016, 262 eligible patients were treated (48 patients in the dose-escalation phase and 214 in the dose-expansion phase). 202 (77%) of 262 patients have completed treatment and follow-up is ongoing. During dose escalation, nivolumab showed a manageable safety profile, including acceptable tolerability. In this phase, 46 (96%) of 48 patients discontinued treatment, 42 (88%) due to disease progression. Incidence of treatment-related adverse events did not seem to be associated with dose and no maximum tolerated dose was reached. 12 (25%) of 48 patients had grade 3/4 treatment-related adverse events. Three (6%) patients had treatment-related serious adverse events (pemphigoid, adrenal insufficiency, liver disorder). 30 (63%) of 48 patients in the dose-escalation phase died (not determined to be related to nivolumab therapy). Nivolumab 3 mg/kg was chosen for dose expansion. The objective response rate was 20% (95% CI 15–26) in patients treated with nivolumab 3 mg/kg in the dose-expansion phase and 15% (95% CI 6–28) in the dose-escalation phase. Nivolumab had a manageable safety profile and no new signals were observed in patients with advanced hepatocellular carcinoma. Durable objective responses show the potential of nivolumab for treatment of advanced hepatocellular carcinoma. Bristol-Myers Squibb.

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Nivolumab in Previously Untreated Melanoma withoutBRAFMutation

Caroline Robert, Georgina V Long, Benjamin Brady … (2015)

Nivolumab was associated with higher rates of objective response than chemotherapy in a phase 3 study involving patients with ipilimumab-refractory metastatic melanoma. The use of nivolumab in previously untreated patients with advanced melanoma has not been tested in a phase 3 controlled study. We randomly assigned 418 previously untreated patients who had metastatic melanoma without a BRAF mutation to receive nivolumab (at a dose of 3 mg per kilogram of body weight every 2 weeks and dacarbazine-matched placebo every 3 weeks) or dacarbazine (at a dose of 1000 mg per square meter of body-surface area every 3 weeks and nivolumab-matched placebo every 2 weeks). The primary end point was overall survival. At 1 year, the overall rate of survival was 72.9% (95% confidence interval [CI], 65.5 to 78.9) in the nivolumab group, as compared with 42.1% (95% CI, 33.0 to 50.9) in the dacarbazine group (hazard ratio for death, 0.42; 99.79% CI, 0.25 to 0.73; P<0.001). The median progression-free survival was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group (hazard ratio for death or progression of disease, 0.43; 95% CI, 0.34 to 0.56; P<0.001). The objective response rate was 40.0% (95% CI, 33.3 to 47.0) in the nivolumab group versus 13.9% (95% CI, 9.5 to 19.4) in the dacarbazine group (odds ratio, 4.06; P<0.001). The survival benefit with nivolumab versus dacarbazine was observed across prespecified subgroups, including subgroups defined by status regarding the programmed death ligand 1 (PD-L1). Common adverse events associated with nivolumab included fatigue, pruritus, and nausea. Drug-related adverse events of grade 3 or 4 occurred in 11.7% of the patients treated with nivolumab and 17.6% of those treated with dacarbazine. Nivolumab was associated with significant improvements in overall survival and progression-free survival, as compared with dacarbazine, among previously untreated patients who had metastatic melanoma without a BRAF mutation. (Funded by Bristol-Myers Squibb; CheckMate 066 ClinicalTrials.gov number, NCT01721772.).

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Author and article information

Journal

Journal ID (nlm-ta): Int J Oncol

Journal ID (iso-abbrev): Int J Oncol

Journal ID (publisher-id): IJO

Title: International Journal of Oncology

Publisher: D.A. Spandidos

ISSN (Print): 1019-6439

ISSN (Electronic): 1791-2423

Publication date Collection: December 2023

Publication date (Electronic): 27 October 2023

Publication date PMC-release: 27 October 2023

Volume: 63

Issue: 6

Electronic Location Identifier: 137

Affiliations

Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China

Author notes

Correspondence to: Dr Fuyu Li or Dr Haijie Hu, Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, 37 Guoxue Road, Chengdu, Sichuan 610041, P.R. China, E-mail: lfy_74@ 123456hotmail.com , E-mail: hhj1063557621@ 123456163.com

Article

Publisher ID: ijo-63-06-05585

DOI: 10.3892/ijo.2023.5585

PMC ID: 10631767

PubMed ID: 37888583

SO-VID: f60e4dfb-dfe5-4d98-9d30-895cb9f7d655

License:

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

History

Date received : 20 April 2023

Date accepted : 12 October 2023

Funding

Funded by: West China Hospital, Sichuan University

Award ID: ZYJC21046

Funded by: West China Hospital, Sichuan University

Award ID: 2021HXFH001

Funded by: Natural Science Foundation of Sichuan Province

Award ID: 2022NSFSC0806

Funded by: National Natural Science Foundation of China for Young Scientists Fund

Award ID: 82203782

Funded by: Sichuan Science and Technology Program

Award ID: 2021YJ0132

Award ID: 2021YFS0100

Funded by: China Postdoctoral Science Foundation

Award ID: 2021M692277

Funded by: Sichuan University-Zigong School-local Cooperation project

Award ID: 2021CDZG-23

Funded by: Science and Technology project of the Health planning committee of Sichuan

Award ID: 21PJ046

Funded by: Post-Doctor Research Project, West China Hospital, Sichuan University

Award ID: 2021HXBH127

The present study was supported by the 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (grant no. ZYJC21046); the 1.3.5 project for disciplines of excellence-Clinical Research Incubation Project, West China Hospital, Sichuan University (grant no. 2021HXFH001); the Natural Science Foundation of Sichuan Province (grant no. 2022NSFSC0806); the National Natural Science Foundation of China for Young Scientists Fund (grant no. 82203782), Sichuan Science and Technology Program (grant nos. 2021YJ0132 and 2021YFS0100); the fellowship of China Postdoctoral Science Foundation (grant no. 2021M692277); the Sichuan University-Zigong School-local Cooperation project (grant no. 2021CDZG-23); the Science and Technology project of the Health planning committee of Sichuan (21PJ046); and the Post-Doctor Research Project, West China Hospital, Sichuan University (grant no. 2021HXBH127).

Tumor immune microenvironment and the current immunotherapy of cholangiocarcinoma (Review)

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Abstract

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Cancer Immunotherapy

Most cited references 196

Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial

Nivolumab in Previously Untreated Melanoma withoutBRAFMutation

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