Generic placeholder image

Current Medicinal Chemistry

Author(s): Huina Shi, Zhaosheng Li and Mingchen Zhu*

DOI: 10.2174/0109298673296618240424095548

DownloadDownload PDF Flyer Cite As
Circulating Immune Cells Predict Prognosis and Clinical Response to Chemotherapy in Cholangiocarcinoma

Page: [595 - 607] Pages: 13

  • * (Excluding Mailing and Handling)

Explore Articles
About Journal
For Authors
For Editors
For Reviewers

Abstract

Background: The immune system is linked to the prognosis and response to treatment of patients with cancer. However, the clinical implication of peripheral blood immune cells in cholangiocarcinoma (CCA) remains vague. Thus, we aimed to assess whether peripheral circulating immune cells could be used as an indicator for prognosis and chemotherapeutic efficacy in CCA.

Methods: The distributions of immune subsets were analyzed in peripheral blood samples from 141 patients with CCA and 131 healthy volunteers by using flow cytometry. The variation in the subset distribution in the two groups and the relationship between clinicopathological features and the subpopulations were investigated. Meanwhile, we assessed the implications of lymphocyte subsets as predictors of chemotherapy outcomes and overall survival (OS).

Results: The proportion of total lymphocytes decreased, while the percentages of activated T cells as well as CD4+CD25+ regulatory T cells (Tregs) increased in CCA. Notably, lymphocyte proportion decreased in patients with regional lymph node (N) (p=0.016) and distant metastasis (M) (p= 0.001). Furthermore, our study showed that peripheral blood lymphocyte subsets were significantly correlated with chemotherapy efficacy, with increased proportions of CD3+ cells (p=0.021) and CD4+ cells (p=0.016) in the effective group. Finally, the Kaplan-Meier analysis indicated that patients with high natural killer (NK) cell proportion might have prolonged OS (p = 0.028).

Conclusion: The relationship between circulating immune cells with prognosis and chemotherapy response in patients with CCA highlights their potential application as an indicator of CCA prognosis and stratification of chemotherapy response.

Keywords: Cholangiocarcinoma, circulating immune cells, prognosis, biomarker, chemotherapy, hepatectomy.

[1]
Valle JW, Kelley RK, Nervi B, Oh DY, Zhu AX. Biliary tract cancer. Lancet 2021; 397(10272): 428-44.
[http://dx.doi.org/10.1016/S0140-6736(21)00153-7] [PMID: 33516341]
[2]
Banales JM, Cardinale V, Carpino G, et al. Cholangiocarcinoma: Current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol 2016; 13(5): 261-80.
[http://dx.doi.org/10.1038/nrgastro.2016.51] [PMID: 27095655]
[3]
Blechacz B, Gores GJ. Cholangiocarcinoma: Advances in pathogenesis, diagnosis, and treatment. Hepatology 2008; 48(1): 308-21.
[http://dx.doi.org/10.1002/hep.22310] [PMID: 18536057]
[4]
Marsh RW, Alonzo M, Bajaj S, et al. Comprehensive review of the diagnosis and treatment of biliary tract cancer 2012. PART I: Diagnosis-clinical staging and pathology. J Surg Oncol 2012; 106(3): 332-8.
[http://dx.doi.org/10.1002/jso.23028] [PMID: 22488652]
[5]
Primrose JN, Fox RP, Palmer DH, et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): A randomised, controlled, multicentre, phase 3 study. Lancet Oncol 2019; 20(5): 663-73.
[http://dx.doi.org/10.1016/S1470-2045(18)30915-X] [PMID: 30922733]
[6]
Gentile D, Donadon M, Lleo A, et al. Surgical treatment of hepatocholangiocarcinoma: A systematic review. Liver Cancer 2020; 9(1): 15-27.
[http://dx.doi.org/10.1159/000503719] [PMID: 32071906]
[7]
Eckel F, Brunner T, Jelic S, Group EGW. Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2011; 22 (Suppl. 6): vi40-4.
[http://dx.doi.org/10.1093/annonc/mdr375] [PMID: 21908502]
[8]
Thongprasert S. The role of chemotherapy in cholangiocarcinoma. Ann Oncol 2005; 16 (Suppl. 2): ii93-6.
[http://dx.doi.org/10.1093/annonc/mdi712] [PMID: 15958484]
[9]
Rizzo A, Frega G, Ricci AD, et al. Anti-EGFR monoclonal antibodies in advanced biliary tract cancer: A systematic review and meta-analysis. In vivo 2020; 34(2): 479-88.
[http://dx.doi.org/10.21873/invivo.11798] [PMID: 32111744]
[10]
Rizzo A, Ricci AD, Brandi G. Recent advances of immunotherapy for biliary tract cancer. Expert Rev Gastroenterol Hepatol 2021; 15(5): 527-36.
[http://dx.doi.org/10.1080/17474124.2021.1853527] [PMID: 33215952]
[11]
Rizzo A, Ricci AD, Brandi G. PD-L1, TMB, MSI, and other predictors of response to immune checkpoint inhibitors in biliary tract cancer. Cancers (Basel) 2021; 13(3): 558.
[http://dx.doi.org/10.3390/cancers13030558] [PMID: 33535621]
[12]
Galon J, Pagès F, Marincola FM, et al. The immune score as a new possible approach for the classification of cancer. J Transl Med 2012; 10(1): 1-4.
[http://dx.doi.org/10.1186/1479-5876-10-1] [PMID: 22214470]
[13]
Tran E, Turcotte S, Gros A, et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 2014; 344(6184): 641-5.
[http://dx.doi.org/10.1126/science.1251102] [PMID: 24812403]
[14]
Ye Y, Zhou L, Xie X, Jiang G, Xie H, Zheng S. Interaction of B7-H1 on intrahepatic cholangiocarcinoma cells with PD-1 on tumor-infiltrating T cells as a mechanism of immune evasion. J Surg Oncol 2009; 100(6): 500-4.
[http://dx.doi.org/10.1002/jso.21376] [PMID: 19697355]
[15]
Goeppert B, Frauenschuh L, Zucknick M, et al. Prognostic impact of tumour-infiltrating immune cells on biliary tract cancer. Br J Cancer 2013; 109(10): 2665-74.
[http://dx.doi.org/10.1038/bjc.2013.610] [PMID: 24136146]
[16]
Oshikiri T, Miyamoto M, Shichinohe T, et al. Prognostic value of intratumoral CD8 + T lymphocyte in extrahepatic bile duct carcinoma as essential immune response. J Surg Oncol 2003; 84(4): 224-8.
[http://dx.doi.org/10.1002/jso.10321] [PMID: 14756433]
[17]
Miura T, Yoshizawa T, Hirai H, et al. Prognostic impact of CD163+ macrophages in tumor stroma and CD8+ T- cells in cancer cell nests in invasive extrahepatic bile duct cancer. Anticancer Res 2017; 37(1): 183-90.
[http://dx.doi.org/10.21873/anticanres.11304] [PMID: 28011489]
[18]
Lim YJ, Koh J, Kim K, et al. High ratio of programmed cell death protein 1 (PD-1)+/CD8+ tumor-infiltrating lymphocytes identifies a poor prognostic subset of extrahepatic bile duct cancer undergoing surgery plus adjuvant chemoradiotherapy. Radiother Oncol 2015; 117(1): 165-70.
[http://dx.doi.org/10.1016/j.radonc.2015.07.003] [PMID: 26235847]
[19]
Takagi S, Miyagawa S, Ichikawa E, et al. Dendritic cells, T-cell infiltration, and grp94 expression in cholangiocellular carcinoma. Hum Pathol 2004; 35(7): 881-6.
[http://dx.doi.org/10.1016/j.humpath.2004.03.016] [PMID: 15257553]
[20]
Ma K, Sun Z, Li X, Guo J, Wang Q, Teng M. Forkhead box M1 recruits FoxP3 + Treg cells to induce immune escape in hilar cholangiocarcinoma. Immun Inflamm Dis 2022; 10(11): e727.
[http://dx.doi.org/10.1002/iid3.727] [PMID: 36301031]
[21]
Kitano Y, Okabe H, Yamashita Y, et al. Tumour-infiltrating inflammatory and immune cells in patients with extrahepatic cholangiocarcinoma. Br J Cancer 2018; 118(2): 171-80.
[http://dx.doi.org/10.1038/bjc.2017.401] [PMID: 29123259]
[22]
Wargo JA, Reddy SM, Reuben A, Sharma P. Monitoring immune responses in the tumor microenvironment. Curr Opin Immunol 2016; 41: 23-31.
[http://dx.doi.org/10.1016/j.coi.2016.05.006] [PMID: 27240055]
[23]
Griffiths JI, Wallet P, Pflieger LT, et al. Circulating immune cell phenotype dynamics reflect the strength of tumor-immune cell interactions in patients during immunotherapy. Proc Natl Acad Sci USA 2020; 117(27): 16072-82.
[http://dx.doi.org/10.1073/pnas.1918937117] [PMID: 32571915]
[24]
Audia S, Nicolas A, Cathelin D, et al. Increase of CD4+CD25+ regulatory T cells in the peripheral blood of patients with metastatic carcinoma: A Phase I clinical trial using cyclophosphamide and immunotherapy to eliminate CD4+CD25+ T lymphocytes. Clin Exp Immunol 2007; 150(3): 523-30.
[http://dx.doi.org/10.1111/j.1365-2249.2007.03521.x] [PMID: 17956583]
[25]
Holm JS, Funt SA, Borch A, et al. Neoantigen-specific CD8 T cell responses in the peripheral blood following PD-L1 blockade might predict therapy outcome in metastatic urothelial carcinoma. Nat Commun 2022; 13(1): 1935.
[http://dx.doi.org/10.1038/s41467-022-29342-0] [PMID: 35410325]
[26]
Tada N, Kawai K, Tsuno NH, et al. Prediction of the preoperative chemoradiotherapy response for rectal cancer by peripheral blood lymphocyte subsets. World J Surg Oncol 2015; 13(1): 30.
[http://dx.doi.org/10.1186/s12957-014-0418-0] [PMID: 25890185]
[27]
Wu Y, Ye S, Goswami S, et al. Clinical significance of peripheral blood and tumor tissue lymphocyte subsets in cervical cancer patients. BMC Cancer 2020; 20(1): 173.
[http://dx.doi.org/10.1186/s12885-020-6633-x] [PMID: 32131750]
[28]
Ottonello S, Genova C, Cossu I, et al. Association between response to nivolumab treatment and peripheral blood lymphocyte subsets in patients with non-small cell lung cancer. Front Immunol 2020; 11: 125.
[http://dx.doi.org/10.3389/fimmu.2020.00125] [PMID: 32117275]
[29]
Mao F, Yang C, Luo W, Wang Y, Xie J, Wang H. Peripheral blood lymphocyte subsets are associated with the clinical outcomes of prostate cancer patients. Int Immunopharmacol 2022; 113: 109287.
[http://dx.doi.org/10.1016/j.intimp.2022.109287]
[30]
Xu Y, Li Z, Shi H, Zhu M. Clinicopathological and prognostic significance of circulating immune cells in the patients with pancreatic cancer. Int Immunopharmacol 2022; 111: 109157.
[http://dx.doi.org/10.1016/j.intimp.2022.109157] [PMID: 35988520]
[31]
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45(2): 228-47.
[http://dx.doi.org/10.1016/j.ejca.2008.10.026] [PMID: 19097774]
[32]
Brindley PJ, Bachini M, Ilyas SI, et al. Cholangiocarcinoma. Nat Rev Dis Primers 2021; 7(1): 65.
[http://dx.doi.org/10.1038/s41572-021-00300-2] [PMID: 34504109]
[33]
Salgado R, Denkert C, Demaria S, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: Recommendations by an International TILs Working Group 2014. Ann Oncol 2015; 26(2): 259-71.
[http://dx.doi.org/10.1093/annonc/mdu450] [PMID: 25214542]
[34]
Hwang M, Canzoniero JV, Rosner S, et al. Peripheral blood immune cell dynamics reflect antitumor immune responses and predict clinical response to immunotherapy. J Immunother Cancer 2022; 10(6): e004688.
[http://dx.doi.org/10.1136/jitc-2022-004688] [PMID: 35688557]
[35]
Stankovic B, Bjørhovde HAK, Skarshaug R, et al. Immune cell composition in human non-small cell lung cancer. Front Immunol 2019; 9: 3101.
[http://dx.doi.org/10.3389/fimmu.2018.03101] [PMID: 30774636]
[36]
Dunne MR, Michielsen AJ, O’Sullivan KE, et al. HLA-DR expression in tumor epithelium is an independent prognostic indicator in esophageal adenocarcinoma patients. Cancer Immunol Immunother 2017; 66(7): 841-50.
[http://dx.doi.org/10.1007/s00262-017-1983-1] [PMID: 28315927]
[37]
Chen DS, Mellman I. Oncology meets immunology: The cancer-immunity cycle. Immunity 2013; 39(1): 1-10.
[http://dx.doi.org/10.1016/j.immuni.2013.07.012] [PMID: 23890059]
[38]
Kim JH, Lee KJ, Lee SW. Cancer immunotherapy with T-cell targeting cytokines: IL-2 and IL-7. BMB Rep 2021; 54(1): 21-30.
[http://dx.doi.org/10.5483/BMBRep.2021.54.1.257] [PMID: 33407991]
[39]
Viallard JF, Blanco P, André M, et al. CD8+HLA-DR+ T lymphocytes are increased in common variable immunodeficiency patients with impaired memory B-cell differentiation. Clin Immunol 2006; 119(1): 51-8.
[http://dx.doi.org/10.1016/j.clim.2005.11.011] [PMID: 16413828]
[40]
Baecher-Allan C, Wolf E, Hafler DA. MHC class II expression identifies functionally distinct human regulatory T cells. J Immunol 2006; 176(8): 4622-31.
[http://dx.doi.org/10.4049/jimmunol.176.8.4622] [PMID: 16585553]
[41]
Zhang G, Xu M, Song Y, Su Z, Zhang H, Zhang C. TNF-α produced by SEC2 mutant (SAM-3)-activated human T cells induces apoptosis of HepG2 cells. Appl Microbiol Biotechnol 2016; 100(6): 2677-84.
[http://dx.doi.org/10.1007/s00253-015-7104-1] [PMID: 26536876]
[42]
Togashi Y, Nishikawa H, Regulatory T. Regulatory T Cells: Molecular and cellular basis for immunoregulation. Curr Top Microbiol Immunol 2017; 410: 3-27.
[http://dx.doi.org/10.1007/82_2017_58] [PMID: 28879523]
[43]
Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell 2008; 133(5): 775-87.
[http://dx.doi.org/10.1016/j.cell.2008.05.009] [PMID: 18510923]
[44]
Sasada T, Kimura M, Yoshida Y, Kanai M, Takabayashi A. CD4+ CD25+ regulatory T cells in patients with gastrointestinal malignancies. Cancer 2003; 98(5): 1089-99.
[http://dx.doi.org/10.1002/cncr.11618] [PMID: 12942579]
[45]
Wolf AM, Wolf D, Steurer M, Gastl G, Gunsilius E, Grubeck-Loebenstein B. Increase of regulatory T cells in the peripheral blood of cancer patients. Clin Cancer Res 2003; 9(2): 606-12.
[PMID: 12576425]
[46]
Tanaka H, Tanaka J, Kjaergaard J, Shu S. Depletion of CD4+ CD25+ regulatory cells augments the generation of specific immune T cells in tumor-draining lymph nodes. J Immunother 2002; 25(3): 207-17.
[http://dx.doi.org/10.1097/00002371-200205000-00003] [PMID: 12000862]
[47]
Alvisi G, Termanini A, Soldani C, et al. Multimodal single-cell profiling of intrahepatic cholangiocarcinoma defines hyperactivated Tregs as a potential therapeutic target. J Hepatol 2022; 77(5): 1359-72.
[http://dx.doi.org/10.1016/j.jhep.2022.05.043] [PMID: 35738508]
[48]
Fogar P, Sperti C, Basso D, et al. Decreased total lymphocyte counts in pancreatic cancer: An index of adverse outcome. Pancreas 2006; 32(1): 22-8.
[http://dx.doi.org/10.1097/01.mpa.0000188305.90290.50] [PMID: 16340740]
[49]
Aquilani R, Brugnatelli S, Maestri R, et al. Peripheral blood lymphocyte percentage may predict chemotolerance and survival in patients with advanced pancreatic cancer. association between adaptive immunity and nutritional state. Curr Oncol 2021; 28(5): 3280-96.
[http://dx.doi.org/10.3390/curroncol28050285] [PMID: 34449579]
[50]
Iseki Y, Shibutani M, Maeda K, et al. The impact of the preoperative peripheral lymphocyte count and lymphocyte percentage in patients with colorectal cancer. Surg Today 2017; 47(6): 743-54.
[http://dx.doi.org/10.1007/s00595-016-1433-2] [PMID: 27783149]
[51]
Godet Y, Fabre E, Dosset M, et al. Analysis of spontaneous tumor-specific CD4 T-cell immunity in lung cancer using promiscuous HLA-DR telomerase-derived epitopes: Potential synergistic effect with chemotherapy response. Clin Cancer Res 2012; 18(10): 2943-53.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-3185] [PMID: 22407833]
[52]
Dewyer NA, Wolf GT, Light E, et al. Circulating CD4-positive lymphocyte levels as predictor of response to induction chemotherapy in patients with advanced laryngeal cancer. Head Neck 2014; 36(1): 9-14.
[http://dx.doi.org/10.1002/hed.23263] [PMID: 23765859]
[53]
Wang W, Erbe AK, Hank JA, Morris ZS, Sondel PM. Cell-Mediated Antibody-Dependent Cellular Cytotoxicity, N.K. NK cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy. Front Immunol 2015; 6: p. 155000.
[http://dx.doi.org/10.3389/fimmu.2015.00368] [PMID: 26284063]
[54]
Melaiu O, Lucarini V, Cifaldi L, Fruci D. Influence of the Tumor Microenvironment on NK Cell Function in Solid Tumors. Front Immunol 2020; 10: 3038.
[http://dx.doi.org/10.3389/fimmu.2019.03038] [PMID: 32038612]
[55]
Purdy AK, Campbell KS. Natural killer cells and cancer: Regulation by the killer cell Ig-like receptors (KIR). Cancer Biol Ther 2009; 8(23): 2209-18.
[http://dx.doi.org/10.4161/cbt.8.23.10455] [PMID: 19923897]
[56]
Coudert JD, Held W. The role of the NKG2D receptor for tumor immunity. Semin Cancer Biol 2006; 16(5): 333-43.
[http://dx.doi.org/10.1016/j.semcancer.2006.07.008] [PMID: 16914326]
[57]
Diefenbach A, Jensen ER, Jamieson AM, Raulet DH. Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature 2001; 413(6852): 165-71.
[http://dx.doi.org/10.1038/35093109] [PMID: 11557981]
[58]
Tang Y, Xie M, Li K, Li J, Cai Z, Hu B. Prognostic value of peripheral blood natural killer cells in colorectal cancer. BMC Gastroenterol 2020; 20(1): 1.: 8.
[http://dx.doi.org/10.1186/s12876-020-1177-8] [PMID: 32028908]
[59]
Nersesian S, Schwartz SL, Grantham SR, et al. NK cell infiltration is associated with improved overall survival in solid cancers: A systematic review and meta-analysis. Transl Oncol 2021; 14(1): 100930.
[http://dx.doi.org/10.1016/j.tranon.2020.100930] [PMID: 33186888]
[60]
Porrata LF. Natural killer cells are key host immune effector cells affecting survival in autologous peripheral blood hematopoietic stem cell transplantation. Cells 2022; 11(21): 3469.
[http://dx.doi.org/10.3390/cells11213469] [PMID: 36359863]
[61]
Shafer D, Smith MR, Borghaei H, et al. Low NK cell counts in peripheral blood are associated with inferior overall survival in patients with follicular lymphoma. Leuk Res 2013; 37(10): 1213-5.
[http://dx.doi.org/10.1016/j.leukres.2013.07.038] [PMID: 23968916]
[62]
He L, Zhu H-Y, Qin S-C, et al. Low natural killer (NK) cell counts in peripheral blood adversely affect clinical outcome of patients with follicular lymphoma. Blood Cancer J 2016; 6(8): e457.
[http://dx.doi.org/10.1038/bcj.2016.67] [PMID: 27518240]
[63]
Wang WT, Zhu HY, Wu YJ, et al. Elevated absolute NK cell counts in peripheral blood predict good prognosis in chronic lymphocytic leukemia. J Cancer Res Clin Oncol 2018; 144(3): 449-57.
[http://dx.doi.org/10.1007/s00432-017-2568-2] [PMID: 29299750]
[64]
Plonquet A, Haioun C, Jais JP, et al. Peripheral blood natural killer cell count is associated with clinical outcome in patients with aaIPI 2–3 diffuse large B-cell lymphoma. Ann Oncol 2007; 18(7): 1209-15.
[http://dx.doi.org/10.1093/annonc/mdm110] [PMID: 17496307]
[65]
Jung IH, Kim DH, Yoo DK, et al. In vivo study of Natural Killer (NK) cell cytotoxicity against cholangiocarcinoma in a nude mouse model. In vivo 2018; 32(4): 771-81.
[http://dx.doi.org/10.21873/invivo.11307] [PMID: 29936458]