Skip to main content

Advertisement

SpringerLink
Log in

Detection and Functional Analysis of Tumor Infiltrating T-Lymphocytes (TIL) in Liver Metastases from Colorectal Cancer

  • Laboratory Research
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

An Erratum to this article was published on 07 February 2009

Abstract

Background

Tumor-infiltrating T lymphocytes (TIL) play an important role in primary colorectal cancer, but their activity in liver metastases has not yet been investigated. The aim of this study was to examine whether tumor-selective infiltration, activation, and cytotoxic activity of TIL can be demonstrated in situ in colorectal liver metastases.

Methods

TIL were obtained from liver metastases and corresponding normal liver tissue of 16 patients with colorectal liver metastases. Characterization of TIL in situ was performed by multicolor flowcytometric analysis. Presence of tumor antigen-reactive T cells was evaluated by interferon gamma Elispot analysis.

Results

TIL in colorectal liver metastases responding against tumor antigens were present in most patients. Although the proportions of CD3+ T cells were comparable in liver metastasis and normal liver tissue, metastases contained significantly enhanced proportions of CD4+ cells (49% vs. 22%, P < .001). Among all CD4+ T helper cells, the proportion of activated (CD4+CD25+) effector cells was significantly increased in liver metastases (15.0% vs. 7.8%, P = .003). Metastases showed significantly higher proportions of activated (CD69+ [70.1% vs. 49.8%, P = .02] and CD25+ [4.1% vs. .6%, P = .06]) and cytotoxically active (CD107a+) CD8+ TIL (3.2% vs. 1.3%, P = .03). Importantly, the presence of activated T helper cells correlated with the frequencies of cytotoxic T lymphocytes that exerted cytotoxic activity in situ (P = .02).

Conclusion

CD4+ and CD8+ TIL are selectively activated in liver metastases, and cytotoxic T lymphocytes exert tumor-selective cytotoxic activity in situ in the presence of activated T helper cells, suggesting the requirement of in-situ-activated T helper cells for efficient cytotoxic T lymphocytes effector function.

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

Similar content being viewed by others

References

  1. Weitz J, Koch M, Debus J, et al. Seminar: colorectal cancer. Lancet 2005;365:153–65

    Article  PubMed  Google Scholar 

  2. Mocellin S, Mandruzzato S, Bronte V, et al. Vaccines for solid tumours. Lancet Oncol 2004;5:681–9

    Article  PubMed  CAS  Google Scholar 

  3. Yang L, Carbone DP. Tumor-host immune interactions and dendritic cell dysfunction. Adv Cancer Res 2004;92:13–27

    Article  PubMed  CAS  Google Scholar 

  4. Parmiani G. Tumor-infiltrating T cells—friend or foe of neoplastic cells? N Engl J Med 2005;353:2640–1

    Article  PubMed  Google Scholar 

  5. Chiba T, Ohtani H, Mizoi T, et al. Intraepithelial CD8+ T-cell count becomes a prognostic factor after a longer follow-up period in human colorectal carcinoma: possible association with suppression of micrometastasis. Br J Cancer 2004;91:1711–7

    PubMed  CAS  Google Scholar 

  6. Naito Y, Saito K, Shiiba K, et al. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 1998;61:3491–4

    Google Scholar 

  7. Menon AG, Janssen-van Rhijn CM, Morreau H, et al. Immune system and prognosis in colorectal cancer: a detailed immunohistochemical analysis. Lab Invest 2004;84:493–501

    Article  PubMed  CAS  Google Scholar 

  8. Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006;313:1960–4

    Article  PubMed  CAS  Google Scholar 

  9. Phillips SM, Banerjea A, Feakins R, et al. Tumour-infiltrating lymphocytes in colorectal cancer with microsatellite instability are activated and cytotoxic. Br J Surg 2004;91:469–75

    Article  PubMed  CAS  Google Scholar 

  10. Pagès F, Berger A, Camus M, et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 2005;353:2654–66

    Article  PubMed  Google Scholar 

  11. Koch M, Beckhove P, Op dW, et al. Tumor infiltrating T lymphocytes in colorectal cancer: tumor-selective activation and cytotoxic activity in situ. Ann Surg 2006;244:986–92

    Article  PubMed  Google Scholar 

  12. Ziegler SF, Ramsdell F, Alderson MR. The activation antigen CD69. Stem Cells 1994;12:456–65

    Article  PubMed  CAS  Google Scholar 

  13. Rubio V, Stuge TB, Singh N, et al. Ex vivo identification, isolation and analysis of tumor-cytolytic T-cells. Nat Med 2003;9:1377–82

    Article  PubMed  CAS  Google Scholar 

  14. Bai L, Beckhove P, Feuerer M, et al. Cognate interactions between memory T cells and tumor antigen-presenting dendritic cells from bone marrow of breast cancer patients: bidirectional cell stimulation, survival and antitumor activity in vivo. Int J Cancer 2003;103:73–83

    Article  PubMed  CAS  Google Scholar 

  15. Solomayer EF, Feuerer M, Bai L, et al. Influence of adjuvant hormone therapy and chemotherapy on the immune system analysed in the bone marrow of patients with breast cancer. Clin Cancer Res 2003;9:174–80

    PubMed  CAS  Google Scholar 

  16. Feuerer M, Beckhove P, Bai L, et al. Therapy of human tumors in NOD/SCID mice with patient-derived reactivated memory T cells from bone marrow. Nat Med 2001;7:452–8

    Article  PubMed  CAS  Google Scholar 

  17. Schmitz-Winnenthal FHVC, Zgraggen K, Galindo L, et al. High frequencies of functional tumor-reactive T cells in bone marrow and blood of pancreatic cancer patients. Cancer Res 2005;65:10079–87

    Article  PubMed  CAS  Google Scholar 

  18. Jarnicki AG, Lysaght J, Todryk S, et al. Suppression of antitumor immunity by IL-10 and TGF-beta-producing T cells infiltrating the growing tumor: influence of tumor environment on the induction of CD4+ and CD8+ regulatory T cells. J Immunol 2006;177:896–904

    PubMed  CAS  Google Scholar 

  19. Diederichsen ACP, Hjelmborg JvB, Christensen PB, et al. Prognostic value of the CD4+/CD8* ratio of tumour infiltrating lymphocytes in colorectal cancer and HLA-DR expression on tumour cells. Cancer Immunol Immun 2003;52:423–8

    CAS  Google Scholar 

  20. Nummer D, Suri-Payer E, Schmitz-Winnenthal H, et al. Role of tumor endothelium in CD4+ CD25+ regulatory T cell infiltration of human pancreatic carcinoma. J Natl Cancer Inst 2007;99:1188–99

    Article  PubMed  CAS  Google Scholar 

  21. Wang RF. Immune suppression by tumor-specific CD4+ regulatory T-cells in cancer. Semin Cancer Biol 2006;16:73–9

    Article  PubMed  CAS  Google Scholar 

  22. Koizumi K, Hojo S, Akashi T, et al. Chemokine receptors in cancer metastasis and cancer cell–derived chemokines in host immune response. Cancer Sci 2007;98:1652–8

    Article  PubMed  CAS  Google Scholar 

  23. Hojo S, Koizumi K, Tsuneyama K, et al. High-level expression of chemokine CXCL16 by tumor cells correlates with a good prognosis and increased tumor-infiltrating lymphocytes in colorectal cancer. Cancer Res 2007;67:4725–31

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgery, University of Heidelberg, INF 110, 69120, Heidelberg, Germany

    Philipp Wagner, Moritz Koch MD, Sylvia Palm, Luis Galindo MD, Daniel Autenrieth, Friedrich H. Schmitz-Winnenthal MD, Markus W. Büchler MD & Jürgen Weitz MD

  2. Division of Cellular Immunology, Tumor Immunology Program, German Cancer Research Center, INF 280, 69120, Heidelberg, Germany

    Daniel Nummer PhD, Volker Schirrmacher PhD & Philipp Beckhove MD

Authors
  1. Philipp Wagner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Moritz Koch MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daniel Nummer PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sylvia Palm
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Luis Galindo MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Daniel Autenrieth
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Friedrich H. Schmitz-Winnenthal MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Volker Schirrmacher PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Markus W. Büchler MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Philipp Beckhove MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jürgen Weitz MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jürgen Weitz MD.

Additional information

P. Wagner and M. Koch contributed equally to this study.

An erratum to this article can be found at http://dx.doi.org/10.1245/s10434-008-0119-4

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wagner, P., Koch, M., Nummer, D. et al. Detection and Functional Analysis of Tumor Infiltrating T-Lymphocytes (TIL) in Liver Metastases from Colorectal Cancer. Ann Surg Oncol 15, 2310–2317 (2008). https://doi.org/10.1245/s10434-008-9971-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-008-9971-5

Keywords

Search

Navigation