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The characteristics of the immune cell profiles in peripheral blood in cholangiocarcinoma patients

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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).

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, 920-8641, Japan

    Akihiko Kida, Eishiro Mizukoshi, Hidenori Kido, Takeshi Terashima, Kuniaki Arai, Tatsuya Yamashita, Kazumi Fushimi, Taro Yamashita, Yoshio Sakai, Masao Honda & Shuichi Kaneko

  2. Department of Nephrology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, 920-8641, Japan

    Tadashi Toyama

  3. Department of Pathology, Toyama Prefectural Central Hospital, Toyama, Toyama, 930-8550, Japan

    Akio Uchiyama

  4. Department of Internal Medicine, Toyama Prefectural Central Hospital, Toyama, Toyama, 930-8550, Japan

    Akito Sakai

  5. Department of Surgery, Toyama Prefectural Central Hospital, Toyama, Toyama, 930-8550, Japan

    Koichi Shimizu

  6. Department of Gastroenterology, JA Toyama Kouseiren Takaoka Hospital, Takaoka, Toyama, 933-0843, Japan

    Akihiko Kida

Authors
  1. Akihiko Kida
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  2. Eishiro Mizukoshi
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Contributions

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.

Corresponding author

Correspondence to Eishiro Mizukoshi.

Ethics declarations

Conflict of interest

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.

Consent to participate

All patients provided written informed consent to participate in this study.

Consent for publication

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

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