In Vitro Evaluation of CMV Specific CD8+T Cells Function in CMV+ Colorectal Cancer Patients Compared to Healthy Controls
-
Mona Shaker Ardakani
,
Fatemeh Pak
,
Parviz Kokhaei
,
Mohammad Sadegh Fazeli
,
Yadollah Shakiba
,
Seyed Morteza Tabatabaei Yazdi
,
Ali Abbasian
,
Maryam Nourizadeh
Abstract
The oncogenic role of human cytomegalovirus (HCMV) has been recently shown in different cancers like colorectal cancer (CRC). According to the recent immunotherapy approach to target the CMV-expressing tumor cells, we investigated the CMV peptide-stimulated CD8+T cells functions in CRC patients compared to healthy individuals. All sixteen patients and seven controls were CMV seropositive. Blood samples were obtained from patients without chemotherapy and radiotherapy before surgery. Cytotoxic CD8+ T cells were generated using 14-day culture of PBMCs in the presences of CMV peptide epitopes and rhIL-2. In addition to the supernatant evaluations for TNF-α and IFN-γ, the functionality of CD8+ T cells was examined by detecting CD107a and intracellular IFN-γ using flow cytometry. CMV DNA was detected in tissues by Real Time PCR. CMV DNA was found in 31% of tumor tissues, while it was not seen in the adjacent non-tumor tissues. There was a close association between CMV in tumor tissue and tumor grade. Surface expression of CD107a and intracellular IFN-γ in CMV-stimulated CD8+T cells and the level of IFN-γ production in patient and control groups increased significantly after culture. The number of functions increased in patients (p<0.05) and healthy individuals after culture. Followingstimulation, expressions of CD107a and intracellular IFN-γ were elevated in tumor CMV positive patients while the TNF-α secretion was decreased. In vitro stimulation of PBMC in the presence of CMV peptide epitopes and IL-2 can be an applicable method to generate cytotoxic CD8+ T cells in CRC patients for future T cell therapy.
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17. Rahbar A, Peredo I, Solberg NW, Taher C, Dzabic M, Xu X, et al. Discordant humoral and cellular immune responses to Cytomegalovirus (CMV) in glioblastoma patients whose tumors are positive for CMV. OncoImmunology 2015; 4(2):e982391.
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20. Ghazi A, Ashoori A, Hanley P, Salsman VS, Shaffer DR, Kew Y, et al. Generation of polyclonal CMV-specific T cells for the adoptive immunotherapy of glioblastoma. J Immunother 2012; 35(2):159-68.
21. Chen HP, Jiang JK, Lai PY, Chen CY, Chou TY, Chen YC, et al. Tumoral presence of human cytomegalovirus is associated with shorter disease‐free survival in elderly patients with colorectal cancer and higher levels of intratumoral interleukin‐17. Clin Microbiol Infect 2014; 20(7):664-71.
22. Criscuoli V, Rizzuto MR, Cottone M. Cytomegalovirus and inflammatory bowel disease: Is there a link? World J Gastroenterol 2006; 12(30):4813-8.
23. Cinatl Jr J, Vogel J-U, Kotchetkov R, Doerr HW. Oncomodulatory signals by regulatory proteins encoded by human cytomegalovirus: a novel role for viral infection in tumor progression. FEMS Microbiol Rev 2004; 28(1):59-77.
24. Chen H-P, Jiang J-K, Chen C-Y, Chou T-Y, Chen Y-C, Chang Y-T, et al. Human cytomegalovirus preferentially infects the neoplastic epithelium of colorectal cancer: a quantitative and histological analysis. J Clin Virol 2012; 54(3):240-4.
25. Dimberg J, Hong TT, Skarstedt M, Löfgren S, Zar N, Matussek A. Detection of cytomegalovirus DNA in colorectal tissue from Swedish and Vietnamese patients with colorectal cancer. Anticancer Res 2013; 33(11):4947-50.
26. Tafvizi F, Fard ZT. Detection of human cytomegalovirus in patients with colorectal cancer by nested-PCR. Asian Pac J Cancer Prev2014; 15(3):1453-7.
27. Bai B, Wang X, Chen E, Zhu H. Human cytomegalovirus infection and colorectal cancer risk: a meta-analysis. Oncotarget 2016; 7(47):76735.
28. Rogers BB, Alpert LC, Hine EA, Buffone GJ. Analysis of DNA in fresh and fixed tissue by the polymerase chain reaction. Am J Pathol 1990; 136(3):541-8.
29. Cai Z-Z, Xu J-G, Zhou Y-H, Zheng J-H, Lin K-Z, Zheng S-Z, et al. Human cytomegalovirus-encoded US28 may act as a tumor promoter in colorectal cancer. World J Gastroenterol 2016; 22(9):2789-98.
30. Inokuma M, dela Rosa C, Schmitt C, Haaland P, Siebert J, Petry D, et al. Functional T cell responses to tumor antigens in breast cancer patients have a distinct phenotype and cytokine signature. J Immunol 2007; 179(4):2627-33.
31. Aktas E, Kucuksezer UC, Bilgic S, Erten G, Deniz G. Relationship between CD107a expression and cytotoxic activity. Cell Immunol 2009; 254(2):149-54.
32. Betts MR, Brenchley JM, Price DA, De Rosa SC, Douek DC, Roederer M, et al. Sensitive and viable identification of antigen-specific CD8+ T cells by a flow cytometric assay for degranulation. J Immunol Methods 2003; 281(1-2):65-78.
33. Trapani JA, Smyth MJ. Functional significance of the perforin/granzyme cell death pathway. Nat Rev Immunol 2002; 2(10):735-47.
34. Precopio ML, Betts MR, Parrino J, Price DA, Gostick E, Ambrozak DR, et al. Immunization with vaccinia virus induces polyfunctional and phenotypically distinctive CD8+ T cell responses. J Exp Med 2007; 204(6):1405-16.
35. Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol 2004; 75(2):163-89.
36. Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular Immunology: with STUDENT CONSULT Online Access: Elsevier Health Sciences; 2014.
37. Wang X, Lin Y. Tumor necrosis factor and cancer, buddies or foes? Acta Pharmacol Sin 2008; 29(11):1275-88.
38. Kim S, Keku TO, Martin C, Galanko J, Woosley JT, Schroeder JC, et al. Circulating levels of inflammatory cytokines and risk of colorectal adenomas. Cancer Res 2008; 68(1):323-8.
39. Stanilov N, Miteva L, Dobreva Z, Stanilova S. Colorectal cancer severity and survival in correlation with tumour necrosis factor-alpha. Biotechnology, Biotechnological Equipment. 2014; 28(5):911-7.
40. Stanilov NS, Dobreva ZG, Stanilova SA. Higher TNF-Alpha Production Detected in Colorectal Cancer Patients Monocytes. Biotechnol Biotechnol Equip 2012; 26(sup1):107-10.
41. Harari A, Cellerai C, Enders FB, Köstler J, Codarri L, Tapia G, et al. Skewed association of polyfunctional antigen-specific CD8 T cell populations with HLA-B genotype. Proc Natl Acad Sci U S A 2007; 104(41):16233-8.
42. Full F, Lehner M, Thonn V, Goetz G, Scholz B, Kaufmann KB, et al. T cells engineered with a cytomegalovirus-specific chimeric immunoreceptor. J Virol 2010; 84(8):4083-8.
2. Chen H-P, Chan Y-J. The oncomodulatory role of human cytomegalovirus in colorectal cancer: implications for clinical trials. Front Oncol 2014; 4:314.
3. Birendra K, Hwang JJ, Farhangfar CJ, Chai SJ. Advances in Immunotherapy in the Treatment of Colorectal Cancer. American Journal of Hematology/Oncology®. 2017;13(7).
4. Jäger D, Jäger E, Knuth A. Immune responses to tumour antigens: implications for antigen specific immunotherapy of cancer. J Clin Pathol 2001; 54(9):669-74.
5. Somers VA, Brandwijk RJ, Joosten B, Moerkerk PT, Arends J-W, Menheere P, et al. A panel of candidate tumor antigens in colorectal cancer revealed by the serological selection of a phage displayed cDNA expression library. J Immunol 2002; 169(5):2772-80.
6. June CH. Adoptive T cell therapy for cancer in the clinic. J Clin Invest 2007; 117(6):1466-76.
7. Coulie PG, Van den Eynde BJ, van der Bruggen P, Boon T. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat Rev Cancer 2014; 14(2):135-46.
8. Mesri EA, Feitelson MA, Munger K. Human viral oncogenesis: a cancer hallmarks analysis. Cell Host Microbe 2014; 15(3):266-82.
9. Şevik M. Oncogenic viruses and mechanisms of oncogenesis. Turkish Journal of Veterinary and Animal Sciences 2012; 36(4):323-9.
10. Ramos JC, Lossos IS. Newly Emerging Therapies Targeting Viral-Related Lymphomas. Curr Oncol Rep 2011; 13(5):416-26.
11. zur Hausen H. The search for infectious causes of human cancers: where and why. Virology 2009; 392(1):1-10.
12. Herbein G, Kumar A. The oncogenic potential of human cytomegalovirus and breast cancer. Front Oncol 2014; 4:230.
13. Shaiegan M, Rasouli M, Zadsar M, Zolfaghari S. Meta-analysis of cytomegalovirus seroprevalence in volunteer blood donors and healthy subjects in Iran from 1992 to 2013. Iran J Basic Med Sci 2015; 18(7):627-34.
14. van Zuylen WJ, Hamilton ST, Naing Z, Hall B, Shand A, Rawlinson WD. Congenital cytomegalovirus infection: Clinical presentation, epidemiology, diagnosis and prevention. Obstet Med 2014; 7(4):140-6.
15. Breda G, Almeida B, Carstensen S, Bonfim CM, Nogueira MB, Vidal LR, et al. Human cytomegalovirus detection by real-time PCR and pp65-antigen test in hematopoietic stem cell transplant recipients: a challenge in low and middle-income countries. Pathog Glob Health 2013; 107(6):312-9.
16. Michaelis M, Doerr HW, Cinatl J. The story of human cytomegalovirus and cancer: increasing evidence and open questions. Neoplasia 2009; 11(1):1-9.
17. Rahbar A, Peredo I, Solberg NW, Taher C, Dzabic M, Xu X, et al. Discordant humoral and cellular immune responses to Cytomegalovirus (CMV) in glioblastoma patients whose tumors are positive for CMV. OncoImmunology 2015; 4(2):e982391.
18. Schuessler A, Smith C, Beagley L, Boyle GM, Rehan S, Matthews K, et al. Autologous T-cell therapy for cytomegalovirus as a consolidative treatment for recurrent glioblastoma. Cancer res 2014; 74(13):3466-76.
19. Crough T, Beagley L, Smith C, Jones L, Walker DG, Khanna R. Ex vivo functional analysis, expansion and adoptive transfer of cytomegalovirus-specific T-cells in patients with glioblastoma multiforme. Immunol Cell Biol 2012; 90(9):872-80.
20. Ghazi A, Ashoori A, Hanley P, Salsman VS, Shaffer DR, Kew Y, et al. Generation of polyclonal CMV-specific T cells for the adoptive immunotherapy of glioblastoma. J Immunother 2012; 35(2):159-68.
21. Chen HP, Jiang JK, Lai PY, Chen CY, Chou TY, Chen YC, et al. Tumoral presence of human cytomegalovirus is associated with shorter disease‐free survival in elderly patients with colorectal cancer and higher levels of intratumoral interleukin‐17. Clin Microbiol Infect 2014; 20(7):664-71.
22. Criscuoli V, Rizzuto MR, Cottone M. Cytomegalovirus and inflammatory bowel disease: Is there a link? World J Gastroenterol 2006; 12(30):4813-8.
23. Cinatl Jr J, Vogel J-U, Kotchetkov R, Doerr HW. Oncomodulatory signals by regulatory proteins encoded by human cytomegalovirus: a novel role for viral infection in tumor progression. FEMS Microbiol Rev 2004; 28(1):59-77.
24. Chen H-P, Jiang J-K, Chen C-Y, Chou T-Y, Chen Y-C, Chang Y-T, et al. Human cytomegalovirus preferentially infects the neoplastic epithelium of colorectal cancer: a quantitative and histological analysis. J Clin Virol 2012; 54(3):240-4.
25. Dimberg J, Hong TT, Skarstedt M, Löfgren S, Zar N, Matussek A. Detection of cytomegalovirus DNA in colorectal tissue from Swedish and Vietnamese patients with colorectal cancer. Anticancer Res 2013; 33(11):4947-50.
26. Tafvizi F, Fard ZT. Detection of human cytomegalovirus in patients with colorectal cancer by nested-PCR. Asian Pac J Cancer Prev2014; 15(3):1453-7.
27. Bai B, Wang X, Chen E, Zhu H. Human cytomegalovirus infection and colorectal cancer risk: a meta-analysis. Oncotarget 2016; 7(47):76735.
28. Rogers BB, Alpert LC, Hine EA, Buffone GJ. Analysis of DNA in fresh and fixed tissue by the polymerase chain reaction. Am J Pathol 1990; 136(3):541-8.
29. Cai Z-Z, Xu J-G, Zhou Y-H, Zheng J-H, Lin K-Z, Zheng S-Z, et al. Human cytomegalovirus-encoded US28 may act as a tumor promoter in colorectal cancer. World J Gastroenterol 2016; 22(9):2789-98.
30. Inokuma M, dela Rosa C, Schmitt C, Haaland P, Siebert J, Petry D, et al. Functional T cell responses to tumor antigens in breast cancer patients have a distinct phenotype and cytokine signature. J Immunol 2007; 179(4):2627-33.
31. Aktas E, Kucuksezer UC, Bilgic S, Erten G, Deniz G. Relationship between CD107a expression and cytotoxic activity. Cell Immunol 2009; 254(2):149-54.
32. Betts MR, Brenchley JM, Price DA, De Rosa SC, Douek DC, Roederer M, et al. Sensitive and viable identification of antigen-specific CD8+ T cells by a flow cytometric assay for degranulation. J Immunol Methods 2003; 281(1-2):65-78.
33. Trapani JA, Smyth MJ. Functional significance of the perforin/granzyme cell death pathway. Nat Rev Immunol 2002; 2(10):735-47.
34. Precopio ML, Betts MR, Parrino J, Price DA, Gostick E, Ambrozak DR, et al. Immunization with vaccinia virus induces polyfunctional and phenotypically distinctive CD8+ T cell responses. J Exp Med 2007; 204(6):1405-16.
35. Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol 2004; 75(2):163-89.
36. Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular Immunology: with STUDENT CONSULT Online Access: Elsevier Health Sciences; 2014.
37. Wang X, Lin Y. Tumor necrosis factor and cancer, buddies or foes? Acta Pharmacol Sin 2008; 29(11):1275-88.
38. Kim S, Keku TO, Martin C, Galanko J, Woosley JT, Schroeder JC, et al. Circulating levels of inflammatory cytokines and risk of colorectal adenomas. Cancer Res 2008; 68(1):323-8.
39. Stanilov N, Miteva L, Dobreva Z, Stanilova S. Colorectal cancer severity and survival in correlation with tumour necrosis factor-alpha. Biotechnology, Biotechnological Equipment. 2014; 28(5):911-7.
40. Stanilov NS, Dobreva ZG, Stanilova SA. Higher TNF-Alpha Production Detected in Colorectal Cancer Patients Monocytes. Biotechnol Biotechnol Equip 2012; 26(sup1):107-10.
41. Harari A, Cellerai C, Enders FB, Köstler J, Codarri L, Tapia G, et al. Skewed association of polyfunctional antigen-specific CD8 T cell populations with HLA-B genotype. Proc Natl Acad Sci U S A 2007; 104(41):16233-8.
42. Full F, Lehner M, Thonn V, Goetz G, Scholz B, Kaufmann KB, et al. T cells engineered with a cytomegalovirus-specific chimeric immunoreceptor. J Virol 2010; 84(8):4083-8.
| Files | ||
| Issue | Vol 18, No 4 (2019) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v18i4.1416 | |
| PMID | 31522446 | |
| Keywords | ||
| Cytomegalovirus CD107a Interferon gamma (IFN-γ) Solid tumor | ||
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How to Cite
1.
Shaker Ardakani M, Pak F, Kokhaei P, Fazeli MS, Shakiba Y, Tabatabaei Yazdi SM, Abbasian A, Nourizadeh M. In Vitro Evaluation of CMV Specific CD8+T Cells Function in CMV+ Colorectal Cancer Patients Compared to Healthy Controls. Iran J Allergy Asthma Immunol. 2019;18(4):379-392.
