Skip to main content

Advertisement

SpringerLink
Log in

Immune impairment in patients with terminal cancers: influence of cancer treatments and cytomegalovirus infection

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Although immunodeficiency is usually considered a prerequisite of oncogenesis, a detailed immune profile in cancer has not yet been described. Without such profiling, it is not surprising that there is a vast discrepancy in the responses of cancer patients to immunotherapy. Our results show that the integrity of the immune system deteriorates with cancer progression by displaying a trend toward decreasing levels of functional T cells, including CD4, naïve, and central memory T cells, and an expansion of hyporesponsive populations such as CD28− and CMV-specific T cells. One hundred and one patients constitute the study group for the observational study reported in this paper. Forty-eight patients with newly diagnosed stages III and IV and 53 patients with extensively treated stage IV disease. The costimulatory molecules CD27 and CD28 were downregulated in all patients. Among the proinflammatory cytokines (IL-6, TNF-α, IFN-γ), only IL-6 differed significantly among the groups, increasing as the cancer stage progressed. Plasma IL-7 did not differ among the participants. The relative deficits of naïve T cells in cancer patients may be associated with the downregulation of IL-7Rα expression rather than changes in the circulating levels of IL-7. The downregulation of IL-7Rα expression was shown to be associated with increased levels of intracellular CMV. The present study suggests that the immune impairment in patients with cancer is associated with multiple factors, such as the stage of cancer, consequence of CMV infection and impact of treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A (1999) Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401:708–712

    Article  CAS  PubMed  Google Scholar 

  2. Mackay CR, Marston WL, Dudler L (1990) Naive and memory T cells show distinct pathways of lymphocyte recirculation. J Exp Med 171:801–817

    Article  CAS  PubMed  Google Scholar 

  3. Champagne P, Ogg GS, King AS, Knabenhans C, Ellefsen K, Nobile M, Appay V, Rizzardi GP, Fleury S, Lipp M, Forster R, Rowland-Jones S, Sekaly RP, McMichael AJ, Pantaleo G (2001) Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 410:106–111

    Article  CAS  PubMed  Google Scholar 

  4. Lin WW, Karin M (2007) A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest 117:1175–1183

    Article  CAS  PubMed  Google Scholar 

  5. Khan N, Shariff N, Cobbold M, Bruton R, Ainsworth JA, Sinclair AJ, Nayak L, Moss PA (2002) Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals. J Immunol 169:1984–1992

    CAS  PubMed  Google Scholar 

  6. Lee AW, Hertel L, Louie RK, Burster T, Lacaille V, Pashine A, Abate DA, Mocarski ES, Mellins ED (2006) Human cytomegalovirus alters localization of MHC class II and dendrite morphology in mature Langerhans cells. J Immunol 177:3960–3971

    CAS  PubMed  Google Scholar 

  7. Altman JD, Moss PA, Goulder PJ, Barouch DH, McHeyzer-Williams MG, Bell JI, McMichael AJ, Davis MM (1996) Phenotypic analysis of antigen-specific T lymphocytes. Science 274:94–96

    Article  CAS  PubMed  Google Scholar 

  8. Park JH, Yu Q, Erman B, Appelbaum JS, Montoya-Durango D, Grimes HL, Singer A (2004) Suppression of IL7Ralpha transcription by IL-7 and other prosurvival cytokines: a novel mechanism for maximizing IL-7-dependent T cell survival. Immunity 21:289–302

    Article  CAS  PubMed  Google Scholar 

  9. Klebanoff CA, Gattinoni L, Restifo NP (2006) CD8+ T-cell memory in tumor immunology and immunotherapy. Immunol Rev 211:214–224

    Article  CAS  PubMed  Google Scholar 

  10. Klebanoff CA, Gattinoni L, Torabi-Parizi P, Kerstann K, Cardones AR, Finkelstein SE, Palmer DC, Antony PA, Hwang ST, Rosenberg SA, Waldmann TA, Restifo NP (2005) Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc Natl Acad Sci USA 102:9571–9576

    Article  CAS  PubMed  Google Scholar 

  11. Foulds KE, Wu CY, Seder RA (2006) Th1 memory: implications for vaccine development. Immunol Rev 211:58–66

    Article  CAS  PubMed  Google Scholar 

  12. Surh CD, Boyman O, Purton JF, Sprent J (2006) Homeostasis of memory T cells. Immunol Rev 211:154–163

    Article  CAS  PubMed  Google Scholar 

  13. Viola A, Schroeder S, Sakakibara Y, Lanzavecchia A (1999) T lymphocyte costimulation mediated by reorganization of membrane microdomains. Science 283:680–682

    Article  CAS  PubMed  Google Scholar 

  14. Powell DJ Jr, Dudley ME, Robbins PF, Rosenberg SA (2005) Transition of late-stage effector T cells to CD27+CD28+ tumor-reactive effector memory T cells in humans after adoptive cell transfer therapy. Blood 105:241–250

    Article  CAS  PubMed  Google Scholar 

  15. Gattinoni L, Klebanoff CA, Palmer DC, Wrzesinski C, Kerstann K, Yu Z, Finkelstein SE, Theoret MR, Rosenberg SA, Restifo NP (2005) Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells. J Clin Invest 115:1616–1626

    Article  CAS  PubMed  Google Scholar 

  16. Gattinoni L, Powell DJ Jr, Rosenberg SA, Restifo NP (2006) Adoptive immunotherapy for cancer: building on success. Nat Rev Immunol 6:383–393

    Article  CAS  PubMed  Google Scholar 

  17. Tan JT, Ernst B, Kieper WC, LeRoy E, Sprent J, Surh CD (2002) Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8+ cells but are not required for memory phenotype CD4+ cells. J Exp Med 195:1523–1532

    Article  CAS  PubMed  Google Scholar 

  18. Boutboul F, Puthier D, Appay V, Pelle O, Ait-Mohand H, Combadiere B, Carcelain G, Katlama C, Rowland-Jones SL, Debre P, Nguyen C, Autran B (2005) Modulation of interleukin-7 receptor expression characterizes differentiation of CD8 T cells specific for HIV, EBV and CMV. AIDS 19:1981–1986

    Article  CAS  PubMed  Google Scholar 

  19. Kuo CP, Wu CL, Ho HT, Chen CG, Liu SI, Lu YT (2008) Detection of cytomegalovirus reactivation in cancer patients receiving chemotherapy. Clin Microbiol Infect 14:221–227

    Article  CAS  PubMed  Google Scholar 

  20. van Leeuwen EM, de Bree GJ, Remmerswaal EB, Yong SL, Tesselaar K, ten Berge IJ, van Lier RA (2005) IL-7 receptor alpha chain expression distinguishes functional subsets of virus-specific human CD8+ T cells. Blood 106:2091–2098

    Article  PubMed  Google Scholar 

  21. Nikolich-Zugich J (2008) Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nat Rev Immunol 8:512–522

    Article  CAS  PubMed  Google Scholar 

  22. Effros RB, Dagarag M, Spaulding C, Man J (2005) The role of CD8+ T-cell replicative senescence in human aging. Immunol Rev 205:147–157

    Article  CAS  PubMed  Google Scholar 

  23. Messaoudi I, Lemaoult J, Guevara-Patino JA, Metzner BM, Nikolich-Zugich J (2004) Age-related CD8 T cell clonal expansions constrict CD8 T cell repertoire and have the potential to impair immune defense. J Exp Med 200:1347–1358

    Article  CAS  PubMed  Google Scholar 

  24. Wherry EJ, Ha SJ, Kaech SM, Haining WN, Sarkar S, Kalia V, Subramaniam S, Blattman JN, Barber DL, Ahmed R (2007) Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27:670–684

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank to Dr. Mary Jeanne Buttrey for critical review and English revision of this manuscript. This study is supported by Mackay Memorial Hospital, under project MMH-E-96008 and NSC-97-2314-B-195-017.

Conflict of interest statement

None declared.

Author information

Authors and Affiliations

  1. Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan

    I-Hsuan Chen, Chen-Chung Chu, I-Fang Tsai & Fang-Ju Sun

  2. Hospice Palliative Care Center, Mackay Memorial Hospital, Taipei, Taiwan

    Yuen-Liang Lai

  3. Center for General Education, National Yang-Ming University, Taipei, Taiwan

    Yuen-Liang Lai

  4. School of Medicine, Taipei Medical University, Taipei, Taiwan

    Yuen-Liang Lai

  5. Mackay Medicine, Nursing and Management College, Taipei, Taiwan

    Chien-Liang Wu & Yen-Ta Lu

  6. Hematology/Oncology Division, Medical Department, Mackay Memorial Hospital, Taipei, Taiwan

    Yi-Fang Chang

  7. Chest Division, Medical Department, Mackay Memorial Hospital, No. 92, Sec. 2, Chung Shan N. Rd, Taipei, Taiwan

    Chien-Liang Wu & Yen-Ta Lu

Authors
  1. I-Hsuan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuen-Liang Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chien-Liang Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yi-Fang Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chen-Chung Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. I-Fang Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Fang-Ju Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yen-Ta Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yen-Ta Lu.

Additional information

Y.-L. Lai and C.-L. Wu contributed equally to this article.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, IH., Lai, YL., Wu, CL. et al. Immune impairment in patients with terminal cancers: influence of cancer treatments and cytomegalovirus infection. Cancer Immunol Immunother 59, 323–334 (2010). https://doi.org/10.1007/s00262-009-0753-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-009-0753-0

Keywords

Search

Navigation