Skip to main content

Elevated level of peripheral CD8+CD28− T lymphocytes are an independent predictor of progression-free survival in patients with metastatic breast cancer during the course of chemotherapy

Cancer Immunology, Immunotherapy volume 62, pages 1123–1130 (2013)Cite this article

Abstract

Purpose

Suppression of cellular immunity resulting from tumorigenesis and/or therapy might promote cancer cells’ growth, progression and invasion. Here, we explored whether T lymphocyte subtypes from peripheral blood of metastatic breast cancer (MBC) female patients could be used as alternative surrogate markers for cancer progress. Additionally, plasma levels of interleukin (IL)-2, IL-4, IL-6, IL-10, IFN-γ, and transforming growth factor-β1 were quantitated from MBC and healthy volunteers.

Experimental design

This study included 89 female MBC patients during the post-salvage chemotherapy follow-up and 50 age- and sex-matched healthy volunteers as control. The percentages of T lymphocyte subpopulations from peripheral blood and plasma levels of cytokines were measured.

Results

Both CD8+CD28− and CD4+CD25+ were elevated in MBC patients compared to the control cohort (P < 0.05). In contrast, CD3+ and CD8+CD28+cells were significantly lower in MBC patients (P < 0.0001, P = 0.045, respectively). MBC patients had elevated levels of immunosuppressive cytokines IL-6 and IL-10. Patients with elevated CD8+CD28− and CD4+CD25+ cells showed increased levels of IL-6, and only patients with elevated CD8+CD28− had decreased interferon-γ. Univariate analysis indicated increased CD3+CD4+ or CD8+CD28+correlated with prolonged progression-free survival (PFS), while elevated CD8+CD28−associated with shorten PFS. The percent of CD8+CD28− T lymphocytes is an independent predictor for PFS through multivariate analysis.

Conclusions

This study suggests that progressive elevated levels of CD8+CD28− suppressor T lymphocytes represent a novel independent predictor of PFS during post-chemotherapy follow-up.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1

References

  1. Marr LA, Gilham DE, Campbell JD, Fraser AR (2012) Immunology in the clinic review series; focus on cancer: double trouble for tumours: bi-functional and redirected T cells as effective cancer immunotherapies. Clin Exp Immunol 167(2):216–225

    PubMed  Article  CAS  Google Scholar 

  2. Chow MT, Möller A, Smyth MJ (2012) Inflammation and immune surveillance in cancer. Semin Cancer Biol 22(1):23–32

    PubMed  Article  CAS  Google Scholar 

  3. Shiao SL, Ganesan AP, Rugo HS, Coussens LM (2011) Immune microenvironments in solid tumors: new targets for therapy. Genes Dev 25(24):2559–2572

    PubMed  Article  CAS  Google Scholar 

  4. Leber MF, Efferth T (2009) Molecular principles of cancer invasion and metastasis. Int J Oncol 34(4):881–895

    PubMed  CAS  Google Scholar 

  5. Miller FR (1993) Immune mechanisms in the sequential steps of metastasis. Crit Rev Oncog 4(3):293–311

    PubMed  CAS  Google Scholar 

  6. Solomayer EF, Feuerer M, Bai L, Umansky V, Beckhove P, Meyberg GC, Bastert G, Schirrmacher V, Diel IJ (2003) Influence of adjuvant hormone therapy and chemotherapy on the immune system analyzed in the bone marrow of patients with breast cancer. Clin Cancer Res 9(1):174–180

    PubMed  CAS  Google Scholar 

  7. Ceschia T, Beorchia A, Guglielmi R, Mandoliti G, Fongione S, Cereghini M, Tonutti E, Sala PG, Pizzi G (1991) Influence of radiotherapy on lymphocyte subpopulations. Radiol Med 81(4):532–536

    PubMed  CAS  Google Scholar 

  8. Zou W (2006) Regulatory T cells, tumor immunity and immunotherapy. Nat Rev Immunol 6(4):295–307

    PubMed  Article  CAS  Google Scholar 

  9. Woo EY, Chu CS, Goletz TJ, Schlienger K, Yeh H, Coukos G et al (2001) Regulatory CD4+CD25+ T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res 61(12):4766–4772

    PubMed  CAS  Google Scholar 

  10. Ichihara F, Kono K, Takahashi A, Kawaida H, Sugai H, Fujii H (2003) Increased populations of regulatory T cells in peripheral blood and tumor-infiltrating lymphocytes in patients with gastric and esophageal cancers. Clin Cancer Res 9(12):4404–4408

    PubMed  Google Scholar 

  11. Gilberto F, Filaci G, Fravega M, Negrini S, Procopio F, Fenoglio D et al (2004) Nonantigen specific CD8+ T suppressor lymphocytes originate from CD8+CD28− T cells and inhibit both T-cell proliferation and CTL function. Hum Immunol 65(2):142–156

    Article  Google Scholar 

  12. Leong PP, Mohammad R, Ibrahim N, Ithnin H, Abdullah M, Davis WC et al (2006) Phenotyping of lymphocytes expressing regulatory and effector markers in infiltrating ductal carcinoma of the breast. Immunol Lett 102(2):229–236

    PubMed  Article  CAS  Google Scholar 

  13. Wang RF (2008) CD8 + regulatory T cells, their suppressive mechanisms, and regulation in cancer. Hum Immunol 69(11):811–814

    PubMed  Article  CAS  Google Scholar 

  14. Aandahl EM, Torgersen KM, Taskén K (2008) CD8+ regulatory T cells-A distinct T-cell lineage or a transient T-cell phenotype? Hum Immunol 69(11):696–699

    PubMed  Article  CAS  Google Scholar 

  15. Filaci G, Fenoglio D, Fravega M, Ansaldo G, Borgonovo G, Traverso P et al (2007) CD8+CD28− T regulatory lymphocytes inhibiting T cell proliferative and cytotoxic functions infiltrate human cancers. J Immunol 179(7):4323–4334

    PubMed  CAS  Google Scholar 

  16. Melichar B, Tousková M, Solichová D, Králicková P, Kopecký G (2001) CD4 + T-lymphocytopenia and systemic immune activation in patients with primary and secondary liver tumours. Scand J Clin Lab Invest 61(5):363–370

    PubMed  Article  CAS  Google Scholar 

  17. Lissoni P, Brivio F, Ferrante R, Vigore L, Vaghi M, Fumagalli E et al (2000) Circulating immature and mature dendritic cells in relation to lymphocyte subsets in patients with gastrointestinal tract cancer. Int J Biol Markers 15(1):22–25

    PubMed  CAS  Google Scholar 

  18. Melichar B, Jandik P, Krejsek J, Solichova D, Drahosova M, Skopec F et al (1996) Mitogen-induced lymphocyte proliferation and systemic immune activation in cancer patients. Tumori 82(3):218–220

    PubMed  CAS  Google Scholar 

  19. Okita R, Saeki T, Takashima S, Yamaguchi Y, Toge T (2005) CD4 + CD25 + regulatory T cells in the peripheral blood of patients with breast cancer and non-small cell lung cancer. Oncol Rep 14(5):1269–1273

    PubMed  CAS  Google Scholar 

  20. Meloni F, Morosini M, Solari N, Passadore I, Nascimbene C, Novo M et al (2006) Foxp3 Expressing CD4 + CD25 + and CD8 + CD28 − T Regulatory Cells in the Peripheral Blood of Patients with Lung Cancer and Pleural Mesothelioma. Hum Immunol 67(1–2):1–12

    PubMed  Article  CAS  Google Scholar 

  21. Fu J, Xu D, Liu Z, Shi M, Zhao P, Fu B et al (2007) Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 132(7):2328–2339

    PubMed  Article  Google Scholar 

  22. Holcombe RF, Jacobson J, Dakhil SR, Stewart RM, Betzing KS, Kannan K et al (1999) Association of immune parameters with clinical outcome in stage III colon cancer: results of Southwest Oncology Group Protocol 9009. Cancer Immunol Immunother 48(9):533–539

    PubMed  Article  CAS  Google Scholar 

  23. Zaloudik J, Lauerova L, Janakova L, Talac R, Simickova M, Nekulova M et al (1999) Significance of pre-treatment immunological parameters in colorectal cancer patients with unresectable metastases to the liver. Hepatogastroenterology 46(25):220–227

    PubMed  CAS  Google Scholar 

  24. Vesely P, Tousková M, Melichar B (2005) Phenotype of peripheral blood leukocytes and survival of patients with metastatic colorectal cancer. Int J Biol Markers 20(2):126–133

    PubMed  CAS  Google Scholar 

  25. Liu F, Lang R, Zhao J, Zhang X, Pringle GA, Fan Y et al (2011) CD8+ cytotoxic T cell and FOXP3+ regulatory T cell infiltration in relation to breast cancer survival and molecular subtypes. Breast Cancer Res Treat 130(2):645–655

    PubMed  Article  CAS  Google Scholar 

  26. Tiwari M (2010) From tumor immunology to cancer immunotherapy: miles to go. J Cancer Res Ther 6(4):427–431

    PubMed  Article  Google Scholar 

  27. Duray A, Demoulin S, Hubert P, Delvenne P, Saussez S (2010) Immune suppression in head and neck cancers: a review. Clin Dev Immunol. doi:10.1155/2010/701657

    PubMed  Google Scholar 

  28. Kim R, Emi M, Tanabe K, Arihiro K (2006) Tumor-driven evolution of immunosuppressive networks during malignant progression. Cancer Res 66(11):5527–5536

    PubMed  Article  CAS  Google Scholar 

  29. Suzuki K, KadotaK Sima CS, Nitadori J, Rusch VW, Travis WD et al (2013) Clinical impact of immune microenvironment in stage I lung adenocarcinoma: tumor interleukin-12 receptor β2(IL-12Rβ2), IL-7R, and stromal FoxP3/CD3 ratio are independent predictors of recurrence. J Clin Oncol 31(4):490–498

    PubMed  Article  CAS  Google Scholar 

  30. Saison J, Demaret J, Venet F, Chidiac C, Malcus C, Poitevin-Later F et al (2013) CD4+CD25+CD127- assessment as a surrogate phenotype for FOXP3+ regulatory T cells in HIV-1 infected viremic and aviremic subjects. Cytometry B Clin Cytom 84(1):50–54

    PubMed  Google Scholar 

  31. Wang HY, Wang RF (2007) Regulatory T cells and cancer. Curr Opin Immunol 19(2):217–223

    PubMed  Article  CAS  Google Scholar 

  32. Watanabe MA, Oda JM, Amarante MK, Cesar Voltarelli J (2010) Regulatory T cells and breast cancer: implications for immunopathogenesis. Cancer Metastasis Rev 29(4):569–579

    PubMed  Article  CAS  Google Scholar 

  33. Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25 + CD4 + regulatory T cells in immunological tolerance to self and nonself. Nat Immunol 6(4):345–352

    PubMed  Article  CAS  Google Scholar 

  34. Shevach EM (2002) CD4 + CD25 + suppressor T cells: more questions than answers. Nat Rev Immunol 2(6):389–400

    PubMed  CAS  Google Scholar 

  35. Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N et al (2003) Conversion of peripheral CD4 + CD25– naive T cells to CD4 + CD25 + regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 198(12):1875–1886

    PubMed  Article  CAS  Google Scholar 

  36. Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G et al (2002) Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 169(5):2756–2761

    PubMed  CAS  Google Scholar 

  37. Sasada T, Kimura M, Yoshida Y, Kanai M, Takabayashi A (2003) CD4 + CD25 + regulatory T cells in patients with gastrointestinal malignancies: possible involvement of regulatory T cells in disease progression. Cancer 98(5):1089–1099

    PubMed  Article  Google Scholar 

  38. Javia LR, Rosenberg SA (2003) CD4 + CD25 + suppressor lymphocytes in the circulation of patients immunized against melanoma antigens. J Immunother 26(1):85–93

    PubMed  Article  CAS  Google Scholar 

  39. Somasundaram R, Jacob L, Swoboda R, Caputo L, Song H, Basak S et al (2002) Inhibition of cytolytic T lymphocyte proliferation by autologous CD4 + CD25 + regulatory T cells in a colorectal carcinoma patient is mediated by transforming growth factor. Cancer Res 62(18):5267–5272

    PubMed  CAS  Google Scholar 

  40. Kim R, Emi M, Tanabe K (2006) Cancer immunosuppression and autoimmune disease: beyond immunosuppressive networks for tumour immunity. Immunology 119(2):254–264

    PubMed  Article  CAS  Google Scholar 

  41. Qiu YR, Yang CL, Chen LB, Wang Q (2002) Analysis of CD8(+) and CD8(+)CD28(−) cell subsets in patients with hepatocellular carcinoma. Di Yi Jun Yi Da Xue Xue Bao 22(1):72–73

    PubMed  Google Scholar 

  42. Tsukishiro T, Donnenberg AD, Whiteside TL (2003) Rapid turnover of the CD8(+)CD28(−) T-cell subset of effector cells in the circulation of patients with head and neck cancer. Cancer Immunol Immunother 52(10):599–607

    PubMed  Article  Google Scholar 

  43. Strioga M, Pasukoniene V, Characiejus D (2011) CD8 + CD28- and CD8 + CD57 + Tcells and their role in health and disease. Immunology 134(1):17–32

    PubMed  Article  CAS  Google Scholar 

  44. Pagès F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R et al (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Eng J Med 353(25):2654–2666

    Article  Google Scholar 

  45. Karagöz B, Bilgi O, Gümüs M, Erikçi AA, Sayan O, Türken O et al (2010) CD8 + CD28- cells and CD4 + CD25 + regulatory T cells in the peripheral blood of advanced stage lung cancer patients. Med Oncol 27(1):29–33

    PubMed  Article  Google Scholar 

  46. DeBenedette MA, Calderhead DM, Tcherepanova IY, Nicolette CA, Healey DG (2011) Potency of mature CD40L RNA electroporated dendritic cells correlates with IL-12 secretion by tracking multifunctional CD8(+)/CD28(+) cytotoxic T-cell responses in vitro. J Immunother 34(1):45–57

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Dr. Wei Sun for excellent technical assistance in flow cytometric analysis, Amy Hobeika Ph.D. from Duke university medical center, Durham, NC, USA for assistance with language editing. Authors received financial support from Natural Science Foundation of China (No.81172534) and Komen-Duke Project in China (3833989) from Susan G. Komen for the Cure Foundation.

Conflict of interest

No potential conflict of interests were disclosed.

Author information

Affiliations

  1. Department of Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, 52 Fucheng Rd, Beijing, 100142, China

    Guohong Song, Xiaoli Wang, Jun Jia, Yanhua Yuan, Fengling Wan, Xinna Zhou, Huabing Yang & Jun Ren

  2. Capital Medical University Cancer Center, Beijing Shijitan Hospital, 10 TieyiRoad, Beijing, 100038, China

    Xiaoli Wang, Xinna Zhou, Huabing Yang & Jun Ren

  3. Department of Surgery, Duke University Medical Center, 571 Research Drive, Suite 433, Box 2606, Durham, NC, 27710, USA

    Herbert Kim Lyerly

  4. Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, 27710, USA

    Jiezhun Gu

Authors
  1. Guohong Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaoli Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jun Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yanhua Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fengling Wan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xinna Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Huabing Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jun Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jiezhun Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Herbert Kim Lyerly
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jun Ren or Herbert Kim Lyerly.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Song, G., Wang, X., Jia, J. et al. Elevated level of peripheral CD8+CD28− T lymphocytes are an independent predictor of progression-free survival in patients with metastatic breast cancer during the course of chemotherapy. Cancer Immunol Immunother 62, 1123–1130 (2013). https://doi.org/10.1007/s00262-013-1424-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-013-1424-8

Keywords

  • Regulatory T lymphocyte
  • Peripheral blood
  • Metastatic breast cancer
  • Progression-free survival
  • Cytokine