Skip to main content
Erschienen in: Cancer Immunology, Immunotherapy 7/2020

13.03.2020 | Original Article

Differential expression of Tim-3, PD-1, and CCR5 on peripheral T and B lymphocytes in hepatitis C virus-related hepatocellular carcinoma and their impact on treatment outcomes

verfasst von: Asmaa M. Zahran, Helal F. Hetta, Amal Rayan, Abeer Sharaf Eldin, Elham Ahmed Hassan, Hussein Fakhry, Ahmed Soliman, Omnia El-Badawy

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 7/2020

Einloggen, um Zugang zu erhalten

Abstract

Background and objective

Activation of the immune checkpoints and expression of chemokines and chemokine receptors have been reported to promote HCC progression. This study aimed to assess the differential expression of Tim-3, PD-1, and CCR5 on peripheral blood lymphocytes from patients with HCV-related HCC and correlate their expression with the treatment outcomes.

Patients and methods

The study incorporated 40 patients with chronic HCV-related HCC and 40 healthy controls. Patients were radiologically assessed for hepatic focal lesions and portal vein thrombosis. Response to HCC treatment and overall survival (OS) outcomes were determined. The expression of Tim-3, PD-1, and CCR5 among CD19+, CD4+, and CD8+ lymphocytes was assessed by flow cytometry.

Results

Higher frequencies of CD4+ and CD8+ cells expressing each of Tim-3 and PD-1 and PD-1+CD19+ cells were observed in the HCV-related HCC patients in comparison with controls. The highest expression of Tim-3 and PD-1 was by the CD8+ cells. Strong relations were detected among PD-1+CD19+, PD-1+CD4+ and PD-1+CD8+ cells. Elevated levels of PD-1+ lymphocytes were significantly associated with poor treatment response and shorter OS.

Conclusion

Modulation of the expression of immune checkpoints as Tim-3 and PD-1, and of CCR5 on T cells is somehow related to HCC. CD8+ T cells expressing PD-1 were the most relevant to HCC prognosis (OS and treatment response) and could represent a promising target for immune therapy against HCC. Future studies need to focus on exploring PD-1+ B cells and Tim-3+CD4+ cells, which seem to play a significant role in the pathogenesis of HCC.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
Zurück zum Zitat Rayan A, Zahran A, El-Badawy O, Soliman A (2019) P-056 Differential expression of CCR5, TIM3 and PD-1 on peripheral blood T and B lymphocytes from hepatitis C patients with hepatocellular carcinoma and their impact on treatment outcomes. Ann Oncol 30((Supplement_4)):mdz155.055 Rayan A, Zahran A, El-Badawy O, Soliman A (2019) P-056 Differential expression of CCR5, TIM3 and PD-1 on peripheral blood T and B lymphocytes from hepatitis C patients with hepatocellular carcinoma and their impact on treatment outcomes. Ann Oncol 30((Supplement_4)):mdz155.055
4.
Zurück zum Zitat Zahran AM, Abdel-Rahim MH, Refaat A, Sayed M, Othman MM, Khalak LMR, Hetta HF (2020) Circulating hematopoietic stem cells, endothelial progenitor cells and cancer stem cells in hepatocellular carcinoma patients: contribution to diagnosis and prognosis. Acta Oncol 59(1):33–39CrossRefPubMed Zahran AM, Abdel-Rahim MH, Refaat A, Sayed M, Othman MM, Khalak LMR, Hetta HF (2020) Circulating hematopoietic stem cells, endothelial progenitor cells and cancer stem cells in hepatocellular carcinoma patients: contribution to diagnosis and prognosis. Acta Oncol 59(1):33–39CrossRefPubMed
5.
Zurück zum Zitat Chaturvedi VK, Singh A, Dubey SK, Hetta HF, John J, Singh M (2019) Molecular mechanistic insight of hepatitis B virus mediated hepatocellular carcinoma. Microb Pathog 128:184–194CrossRefPubMed Chaturvedi VK, Singh A, Dubey SK, Hetta HF, John J, Singh M (2019) Molecular mechanistic insight of hepatitis B virus mediated hepatocellular carcinoma. Microb Pathog 128:184–194CrossRefPubMed
7.
Zurück zum Zitat Hetta HF, Mekky MA, Khalil NK, Mohamed WA, El-Feky MA, Ahmed SH, Daef EA, Medhat A, Nassar MI, Sherman KE (2016) Extra-hepatic infection of hepatitis C virus in the colon tissue and its relationship with hepatitis C virus pathogenesis. J Med Microbiol 65(8):703CrossRefPubMedPubMedCentral Hetta HF, Mekky MA, Khalil NK, Mohamed WA, El-Feky MA, Ahmed SH, Daef EA, Medhat A, Nassar MI, Sherman KE (2016) Extra-hepatic infection of hepatitis C virus in the colon tissue and its relationship with hepatitis C virus pathogenesis. J Med Microbiol 65(8):703CrossRefPubMedPubMedCentral
8.
Zurück zum Zitat Zahran AM, Nafady-Hego H, Mansor SG, Abbas WA, Abdel-Malek MO, Mekky MA, Hetta HF (2019) Increased frequency and FOXP3 expression of human CD8+ CD25High+ T lymphocytes and its relation to CD4 regulatory T cells in patients with hepatocellular carcinoma. Hum Immunol 80:510–516CrossRefPubMed Zahran AM, Nafady-Hego H, Mansor SG, Abbas WA, Abdel-Malek MO, Mekky MA, Hetta HF (2019) Increased frequency and FOXP3 expression of human CD8+ CD25High+ T lymphocytes and its relation to CD4 regulatory T cells in patients with hepatocellular carcinoma. Hum Immunol 80:510–516CrossRefPubMed
9.
Zurück zum Zitat Hassan EA, Ahmed EH, Nafee AM, El-Gafary N, Hetta HF, El-Mokhtar MA (2019) Regulatory T cells, IL10 and IL6 in HCV related hepatocellular carcinoma after transarterial chemoembolization (TACE). Egypt J Immunol 26:69–78PubMed Hassan EA, Ahmed EH, Nafee AM, El-Gafary N, Hetta HF, El-Mokhtar MA (2019) Regulatory T cells, IL10 and IL6 in HCV related hepatocellular carcinoma after transarterial chemoembolization (TACE). Egypt J Immunol 26:69–78PubMed
10.
Zurück zum Zitat Zahran AM, Ashmawy AM, Rayan A, Elkady A, Elsherbiny NM, Hetta HF (2018) Frequency and implications of natural killer and natural killer T cells in hepatocellular carcinoma. Egypt J Immunol 25:45PubMed Zahran AM, Ashmawy AM, Rayan A, Elkady A, Elsherbiny NM, Hetta HF (2018) Frequency and implications of natural killer and natural killer T cells in hepatocellular carcinoma. Egypt J Immunol 25:45PubMed
13.
Zurück zum Zitat Hetta H, Elkady A, Tohamy T, Badary M (2016) Regulatory B cells: key players in hepatocellular carcinoma progression. Gastroenterol Hepatol Open Access 5(2):00136CrossRef Hetta H, Elkady A, Tohamy T, Badary M (2016) Regulatory B cells: key players in hepatocellular carcinoma progression. Gastroenterol Hepatol Open Access 5(2):00136CrossRef
20.
Zurück zum Zitat Hetta HF, Zahran AM, Mansor SG, Abdel-Malek MO, Mekky MA, Abbas WA (2019) Frequency and implications of myeloid-derived suppressor cells and lymphocyte subsets in Egyptian patients with hepatitis C virus-related hepatocellular carcinoma. J Med Virol 91(7):1319–1328CrossRefPubMed Hetta HF, Zahran AM, Mansor SG, Abdel-Malek MO, Mekky MA, Abbas WA (2019) Frequency and implications of myeloid-derived suppressor cells and lymphocyte subsets in Egyptian patients with hepatitis C virus-related hepatocellular carcinoma. J Med Virol 91(7):1319–1328CrossRefPubMed
22.
Zurück zum Zitat Hetta HF, Khairy H, Ismail S (2017) Circulating IL17A and IFN-gamma serum levels in cirrhotic hepatitis C virus infected patients with autoimmune thyroiditis. Int J Curr Microbiol Appl Sci 6(3):1972–1983CrossRef Hetta HF, Khairy H, Ismail S (2017) Circulating IL17A and IFN-gamma serum levels in cirrhotic hepatitis C virus infected patients with autoimmune thyroiditis. Int J Curr Microbiol Appl Sci 6(3):1972–1983CrossRef
24.
Zurück zum Zitat Nahon P, Sutton A, Rufat P, Simon C, Trinchet JC, Gattegno L, Beaugrand M, Charnaux N (2008) Chemokine system polymorphisms, survival and hepatocellular carcinoma occurrence in patients with hepatitis C virus-related cirrhosis. World J Gastroenterol 14(5):713–719CrossRefPubMedPubMedCentral Nahon P, Sutton A, Rufat P, Simon C, Trinchet JC, Gattegno L, Beaugrand M, Charnaux N (2008) Chemokine system polymorphisms, survival and hepatocellular carcinoma occurrence in patients with hepatitis C virus-related cirrhosis. World J Gastroenterol 14(5):713–719CrossRefPubMedPubMedCentral
30.
Zurück zum Zitat Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T (2000) Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192(7):1027–1034. https://doi.org/10.1084/jem.192.7.1027 CrossRefPubMedPubMedCentral Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T (2000) Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192(7):1027–1034. https://​doi.​org/​10.​1084/​jem.​192.​7.​1027 CrossRefPubMedPubMedCentral
32.
Zurück zum Zitat Liu Y (2018) Immunomodulatory effects of Tim-3 and PD-1 on chronic hepatitis B virus infection. Infect Int 7(1):6–11CrossRef Liu Y (2018) Immunomodulatory effects of Tim-3 and PD-1 on chronic hepatitis B virus infection. Infect Int 7(1):6–11CrossRef
34.
Zurück zum Zitat Golden-Mason L, Palmer BE, Kassam N, Townshend-Bulson L, Livingston S, McMahon BJ, Castelblanco N, Kuchroo V, Gretch DR, Rosen HR (2009) Negative immune regulator Tim-3 is overexpressed on T cells in hepatitis C virus infection and its blockade rescues dysfunctional CD4+ and CD8+ T cells. J Virol 83(18):9122–9130CrossRefPubMedPubMedCentral Golden-Mason L, Palmer BE, Kassam N, Townshend-Bulson L, Livingston S, McMahon BJ, Castelblanco N, Kuchroo V, Gretch DR, Rosen HR (2009) Negative immune regulator Tim-3 is overexpressed on T cells in hepatitis C virus infection and its blockade rescues dysfunctional CD4+ and CD8+ T cells. J Virol 83(18):9122–9130CrossRefPubMedPubMedCentral
35.
Zurück zum Zitat Wu W, Shi Y, Li J, Chen F, Chen Z, Zheng M (2011) Tim-3 expression on peripheral T cell subsets correlates with disease progression in hepatitis B infection. Virol J 8(1):113CrossRefPubMedPubMedCentral Wu W, Shi Y, Li J, Chen F, Chen Z, Zheng M (2011) Tim-3 expression on peripheral T cell subsets correlates with disease progression in hepatitis B infection. Virol J 8(1):113CrossRefPubMedPubMedCentral
37.
Zurück zum Zitat Li H, Wu K, Tao K, Chen L, Zheng Q, Lu X, Liu J, Shi L, Liu C, Wang G, Zou W (2012) Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. Hepatology (Baltimore, MD) 56(4):1342–1351. https://doi.org/10.1002/hep.25777 CrossRef Li H, Wu K, Tao K, Chen L, Zheng Q, Lu X, Liu J, Shi L, Liu C, Wang G, Zou W (2012) Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. Hepatology (Baltimore, MD) 56(4):1342–1351. https://​doi.​org/​10.​1002/​hep.​25777 CrossRef
39.
Zurück zum Zitat He G, Zhang H, Zhou J, Wang B, Chen Y, Kong Y, Xie X, Wang X, Fei R, Wei L (2015) Peritumoural neutrophils negatively regulate adaptive immunity via the PD-L1/PD-1 signalling pathway in hepatocellular carcinoma. J Exp Clin Cancer Res 34(1):141CrossRefPubMedPubMedCentral He G, Zhang H, Zhou J, Wang B, Chen Y, Kong Y, Xie X, Wang X, Fei R, Wei L (2015) Peritumoural neutrophils negatively regulate adaptive immunity via the PD-L1/PD-1 signalling pathway in hepatocellular carcinoma. J Exp Clin Cancer Res 34(1):141CrossRefPubMedPubMedCentral
40.
Zurück zum Zitat Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R (1973) Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 60(8):646–649CrossRefPubMed Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R (1973) Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 60(8):646–649CrossRefPubMed
42.
Zurück zum Zitat Nelson BH (2010) CD20+ B cells: the other tumor-infiltrating lymphocytes. J Immunol 185(9):4977–4982CrossRefPubMed Nelson BH (2010) CD20+ B cells: the other tumor-infiltrating lymphocytes. J Immunol 185(9):4977–4982CrossRefPubMed
44.
Zurück zum Zitat Fukada K, Sobao Y, Tomiyama H, Oka S, Takiguchi M (2002) Functional expression of the chemokine receptor CCR5 on virus epitope-specific memory and effector CD8+ T cells. J Immunol 168(5):2225–2232CrossRefPubMed Fukada K, Sobao Y, Tomiyama H, Oka S, Takiguchi M (2002) Functional expression of the chemokine receptor CCR5 on virus epitope-specific memory and effector CD8+ T cells. J Immunol 168(5):2225–2232CrossRefPubMed
45.
Zurück zum Zitat Luther SA, Cyster JG (2001) Chemokines as regulators of T cell differentiation. Nat Immunol 2(2):102CrossRefPubMed Luther SA, Cyster JG (2001) Chemokines as regulators of T cell differentiation. Nat Immunol 2(2):102CrossRefPubMed
46.
Zurück zum Zitat Butrym A, Kryczek I, Dlubek D, Jaskula E, Lange A, Jurczyszyn A, Mazur G (2018) High expression of CC chemokine receptor 5 (CCR5) promotes disease progression in patients with B-cell non-Hodgkin lymphomas. Curr Probl Cancer 42(2):268–275CrossRefPubMed Butrym A, Kryczek I, Dlubek D, Jaskula E, Lange A, Jurczyszyn A, Mazur G (2018) High expression of CC chemokine receptor 5 (CCR5) promotes disease progression in patients with B-cell non-Hodgkin lymphomas. Curr Probl Cancer 42(2):268–275CrossRefPubMed
48.
Zurück zum Zitat Liu Y, Poon RT, Hughes J, Feng X, Yu WC, Fan ST (2005) Chemokine receptors support infiltration of lymphocyte subpopulations in human hepatocellular carcinoma. Clin Immunol 114(2):174–182CrossRefPubMed Liu Y, Poon RT, Hughes J, Feng X, Yu WC, Fan ST (2005) Chemokine receptors support infiltration of lymphocyte subpopulations in human hepatocellular carcinoma. Clin Immunol 114(2):174–182CrossRefPubMed
50.
Zurück zum Zitat Liu YY, Wang Y, Walsh TR, Yi LX, Zhang R, Spencer J, Doi Y, Tian G, Dong B, Huang X, Yu LF, Gu D, Ren H, Chen X, Lv L, He D, Zhou H, Liang Z, Liu JH, Shen J (2016) Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis 16(2):161–168. https://doi.org/10.1016/S1473-3099(15)00424-7 CrossRefPubMed Liu YY, Wang Y, Walsh TR, Yi LX, Zhang R, Spencer J, Doi Y, Tian G, Dong B, Huang X, Yu LF, Gu D, Ren H, Chen X, Lv L, He D, Zhou H, Liang Z, Liu JH, Shen J (2016) Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis 16(2):161–168. https://​doi.​org/​10.​1016/​S1473-3099(15)00424-7 CrossRefPubMed
53.
Zurück zum Zitat World Health Organization (2017) Global hepatitis report 2017. World Health Organization, Washington World Health Organization (2017) Global hepatitis report 2017. World Health Organization, Washington
54.
Zurück zum Zitat Mekky MA, Abdel-Malek MO, Osman HA, Abdel-Aziz EM, Hashim A-KA, Hetta HF, Morsy KH (2019) Efficacy of ombitasvir/paritaprevir/ritonavir/ribavirin in management of HCV genotype 4 and end-stage kidney disease. Clin Res Hepatol Gastroenterol 43(1):82–87CrossRefPubMed Mekky MA, Abdel-Malek MO, Osman HA, Abdel-Aziz EM, Hashim A-KA, Hetta HF, Morsy KH (2019) Efficacy of ombitasvir/paritaprevir/ritonavir/ribavirin in management of HCV genotype 4 and end-stage kidney disease. Clin Res Hepatol Gastroenterol 43(1):82–87CrossRefPubMed
55.
Zurück zum Zitat Mekky MA, Sayed HI, Abdelmalek MO, Saleh MA, Osman OA, Osman HA, Morsy KH, Hetta HF (2019) Prevalence and predictors of occult hepatitis C virus infection among Egyptian patients who achieved sustained virologic response to sofosbuvir/daclatasvir therapy: a multi-center study. Infect Drug Resist 12:273CrossRefPubMedPubMedCentral Mekky MA, Sayed HI, Abdelmalek MO, Saleh MA, Osman OA, Osman HA, Morsy KH, Hetta HF (2019) Prevalence and predictors of occult hepatitis C virus infection among Egyptian patients who achieved sustained virologic response to sofosbuvir/daclatasvir therapy: a multi-center study. Infect Drug Resist 12:273CrossRefPubMedPubMedCentral
56.
Zurück zum Zitat Mazouz S, Boisvert M, Shoukry NH, Lamarre D (2018) Reversing immune dysfunction and liver damage after direct-acting antiviral treatment for hepatitis C. Can Liver J 1(2):78–105CrossRef Mazouz S, Boisvert M, Shoukry NH, Lamarre D (2018) Reversing immune dysfunction and liver damage after direct-acting antiviral treatment for hepatitis C. Can Liver J 1(2):78–105CrossRef
57.
Zurück zum Zitat Abdel-Hameed EA, Rouster SD, Ji H, Ulm A, Hetta HF, Anwar N, Sherman KE, Shata MTM (2016) Evaluating the role of cellular immune responses in the emergence of HCV NS3 resistance mutations during protease inhibitor therapy. Viral Immunol 29(4):252–258CrossRefPubMedPubMedCentral Abdel-Hameed EA, Rouster SD, Ji H, Ulm A, Hetta HF, Anwar N, Sherman KE, Shata MTM (2016) Evaluating the role of cellular immune responses in the emergence of HCV NS3 resistance mutations during protease inhibitor therapy. Viral Immunol 29(4):252–258CrossRefPubMedPubMedCentral
58.
Zurück zum Zitat Zhang Y, Cai P, Liang T, Wang L, Hu L (2017) TIM-3 is a potential prognostic marker for patients with solid tumors: a systematic review and meta-analysis. Oncotarget 8(19):31705CrossRefPubMedPubMedCentral Zhang Y, Cai P, Liang T, Wang L, Hu L (2017) TIM-3 is a potential prognostic marker for patients with solid tumors: a systematic review and meta-analysis. Oncotarget 8(19):31705CrossRefPubMedPubMedCentral
59.
Zurück zum Zitat Zahran AM, Saleh M, Mostafa F, Sayed MM, Rayan A, Ali AM, Hetta HF (2018) Up-regulation of regulatory T cells, CD200 and TIM3 expression in cytogenetically normal acute myeloid leukemia. Cancer Biomarkers 22(3):587–595CrossRefPubMed Zahran AM, Saleh M, Mostafa F, Sayed MM, Rayan A, Ali AM, Hetta HF (2018) Up-regulation of regulatory T cells, CD200 and TIM3 expression in cytogenetically normal acute myeloid leukemia. Cancer Biomarkers 22(3):587–595CrossRefPubMed
60.
Zurück zum Zitat Ma C, Kesarwala AH, Eggert T, Medina-Echeverz J, Kleiner DE, Jin P, Stroncek DF, Terabe M, Kapoor V, ElGindi M (2016) NAFLD causes selective CD4+ T lymphocyte loss and promotes hepatocarcinogenesis. Nature 531(7593):253CrossRefPubMedPubMedCentral Ma C, Kesarwala AH, Eggert T, Medina-Echeverz J, Kleiner DE, Jin P, Stroncek DF, Terabe M, Kapoor V, ElGindi M (2016) NAFLD causes selective CD4+ T lymphocyte loss and promotes hepatocarcinogenesis. Nature 531(7593):253CrossRefPubMedPubMedCentral
Metadaten
Titel
Differential expression of Tim-3, PD-1, and CCR5 on peripheral T and B lymphocytes in hepatitis C virus-related hepatocellular carcinoma and their impact on treatment outcomes
verfasst von
Asmaa M. Zahran
Helal F. Hetta
Amal Rayan
Abeer Sharaf Eldin
Elham Ahmed Hassan
Hussein Fakhry
Ahmed Soliman
Omnia El-Badawy
Publikationsdatum
13.03.2020
Verlag
Springer Berlin Heidelberg
Erschienen in
Cancer Immunology, Immunotherapy / Ausgabe 7/2020
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-019-02465-y

Weitere Artikel der Ausgabe 7/2020

Cancer Immunology, Immunotherapy 7/2020 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.