Abstract
Background
Immune related cells are known to be closely related to the therapeutic effects and prognoses of cancer patients. In this study, we analyzed immune cell profiles (ICP) of cholangiocarcinoma patients (CCA).
Methods
To measure the frequency of immune cells, peripheral blood mononuclear cells of 41 CCA and 10 healthy volunteers (HV) were analyzed by FACS.
Results
There were significant differences between CCA and HV in ICP, and these differences were a consequence of tumor-bearing status, because many items in ICP before surgery were restored to levels in HV after surgery. Therefore, these changes were specifically attributable to cholangiocarcinoma, and we examined if they can function as biomarkers for therapeutic effects and prognoses. A shorter overall survival was associated with a lower frequency of helper T cells (HT) (p = 0.001), a higher frequency of effector regulatory T cells (eTregs) (p = 0.008), and a lower frequency of CD80 + eTregs (p = 0.024) in the best supportive care group, with a lower frequency of CD25 + naïve Tregs (nTregs) (p = 0.005) in the chemotherapy group, and with a lower frequency of OX40 + HT (p = 0.022), CD25 + CD8 + T cells (p = 0.017), and OX40 + CD8 + T cells (p = 0.032) in the surgery group. The recurrence factors were a higher frequency of CD4 + T cells (p = 0.009), CCR6 + nTregs (p = 0.014), and CXCR3 + nTregs (p = 0.012), and a lower frequency of PD-1 + HT (p = 0.006), OX40 + HT (p = 0.004), CD8 + T cells (p = 0.001), and CTLA-4 + CD8 + T cells (p = 0.036).
Conclusions
The ICP in CCA are specifically attributable to cholangiocarcinoma, and may be biomarkers for therapeutic effects and prognoses.
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Data availability
There are no linked research data sets for this submission. The following reason is given: Date will be available on request.
Abbreviations
- CCA:
-
Cholangiocarcinoma patients
- CTLs:
-
Cytotoxic T lymphocytes
- HCC:
-
Hepatocellular carcinoma
- PBMCs:
-
Peripheral blood mononuclear cells
- Tregs:
-
Regulatory T cells
- MDSCs:
-
Myeloid-derived suppressor cells
- ICP:
-
Immune cell profiles
- CD:
-
Anti-cluster of differentiation
- HV:
-
Healthy volunteers
- HCV SVR12:
-
Hepatitis C virus sustained virological response 12
- iCCA:
-
Intrahepatic cholangiocarcinoma
- pCCA:
-
Perihilar cholangiocarcinoma
- GBCA:
-
Gallbladder carcinoma including cystic duct carcinoma
- dCCA:
-
Distal cholangiocarcinoma
- BSC:
-
Best supportive care
- HBV:
-
Hepatitis B virus infection
- HCV:
-
HCV infection
- DM:
-
Diabetes mellitus
- UICC:
-
Union Internationale Contre Le Cancer
- HLA:
-
Human histocompatibility leukocyte antigen
- FoxP3:
-
Forkhead box P3
- CTLA-4:
-
Cytotoxic T-lymphocyte antigen-4
- PD-1:
-
Programmed cell death-1
- PD-L1:
-
Programmed cell death-1 ligand
- CCR:
-
C–C chemokine receptor
- CXCR3:
-
C-X-C motif chemokine receptor 3
- AST:
-
Aspartate transaminase
- ALT:
-
Alanine transaminase
- γGTP:
-
γ-Glutamyltranspeptidase
- WBC:
-
White blood cell
- ALP:
-
Alkaline phosphatase
- T.bil:
-
Total bilirubin
- CA19-9:
-
Carbohydrate antigen 19-9
- nTregs:
-
Naïve Tregs
- eTregs:
-
Effector Tregs
- OS:
-
Overall survival
- CEA:
-
Carcinoembryonic antigen
- RFS:
-
Recurrence-free survival
- FSC:
-
Forward scatter
- SSC:
-
Side scatter
- pre:
-
Pre-operation group
- post:
-
Post-operation group
- NR:
-
Non-recurrent cholangiocarcinoma patient group
- R:
-
Recurrent cholangiocarcinoma patient group
- before:
-
Before biliary drainage group
- after:
-
After biliary drainage group
- Freq:
-
Frequency
- M:
-
Male
- F:
-
Female
- D.bil:
-
Direct bilirubin
- CRP:
-
C-reactive protein
- PSC:
-
Primary sclerosing cholangitis
- ND:
-
Not determined
- FCS:
-
Heat-inactivated fetal calf serum
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Acknowledgements
The authors thank Taro Kawane, Aya Ito, Michiko Nishino, Saiho Sugimoto, Toshiki Matsuo, Atsuyoshi Mizukami, Masaaki Yano, Fumitaka Arihara, Hironori Hayashi, Koji Amaya, Koichiro Matsuda, Kohei Ogawa, and Mitsuru Matsuda from the Department of Internal Medicine and Surgery of Toyama Prefectural Central Hospital for collecting cholangiocarcinoma samples.
Funding
This study was supported by research grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (25460984).
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Conception and design: AK, EM, TT, KA, TY, TY, YS, MH, and SK. Development of methodology: EM, and SK. Acquisition of data: AK, AU, AS, and KS. Analysis and interpretation of date: AK, and TT. Writing and review of the manuscript: AK, and EM. Administrative, technical, or material support: AK, HK and KF. Study supervision: SK.
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Akihiko Kida declared that no conflict of interest exists. Eishiro Mizukoshi declared that no conflict of interest exists. Hidenori Kido declared that no conflict of interest exists. Tadashi Toyama declared that no conflict of interest exists. Takeshi Terashima declared that no conflict of interest exists. Kuniaki Arai declared that no conflict of interest exists. Tatsuya Yamashita declared that no conflict of interest exists. Kazumi Fushimi declared that no conflict of interest exists. Taro Yamashita declared that no conflict of interest exists. Yoshio Sakai declared that no conflict of interest exists. Masao Honda declared that no conflict of interest exists. Akio Uchiyama declared that no conflict of interest exists. Akito Sakai declared that no conflict of interest exists. Koichi Shimizu declared that no conflict of interest exists. Shuichi Kaneko declared that no conflict of interest exists.
Ethics approval
This study was approved by the ethics committee of Kanazawa University (No.1237), and all patients provided written informed consent to participate in accordance with the Declaration of Helsinki.
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All patients provided written informed consent to participate in this study.
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Consent for publication was received from the patients.
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Kida, A., Mizukoshi, E., Kido, H. et al. The characteristics of the immune cell profiles in peripheral blood in cholangiocarcinoma patients. Hepatol Int 15, 695–706 (2021). https://doi.org/10.1007/s12072-021-10177-8
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DOI: https://doi.org/10.1007/s12072-021-10177-8