Skip to main content

Advertisement

SpringerLink
Log in

Melanoma-specific tumor-infiltrating lymphocytes but not circulating melanoma-specific T cells may predict survival in resected advanced-stage melanoma patients

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

Abstract

Purpose: To study the effect of autologous tumor cell vaccinations on the presence and numbers of circulating CD8+ T cells specific for tumor-associated antigens (TAA) in metastatic melanoma patients. To investigate the correlation between the presence of tumor-infiltrating lymphocytes (TIL) and circulating TAA-specific CD8+ T cells before and after autologous tumor cell vaccination with overall survival. Experimental design: Twenty-five stage III and resected stage IV metastatic melanoma patients were adjuvantly treated with a series of intracutaneously injected autologous tumor cell vaccinations, of which the first two contained BCG as an immunostimulatory adjuvant. Tumor samples and blood samples obtained before and after vaccination of these patients were studied for the presence of TAA-specific T cells using HLA-tetramers and results were correlated with survival. Results: In 5 of 17 (29%) melanoma patients, circulating TAA-specific T cells were detectable prior to immunizations. No significant changes in the frequency and specificity were found during the treatment period in all patients. Presence of circulating TAA-specific T cells was not correlated with survival (log rank, P=0.215). Inside melanoma tissue, TAA-specific TIL could be detected in 75% of 16 available tumor samples. In case of detectable TAA-specific TIL, median survival was 22.5 months compared to median survival of 4.5 months in case of absence of TAA-specific T cells (log rank, P=0.0094). In none of the patients, TAA-specific T cells were found both in tumor tissue and blood at the same time. Conclusions: These data suggest that the presence of TAA-specific TILs forms a prognostic factor, predicting improved survival in advanced-stage melanoma patients. The absence of TAA-specific T cells in the circulation suggests that homing of the tumor-specific T cell population to the tumor site contributes to the effectiveness of antitumor immunity.

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

Similar content being viewed by others

References

  1. Bodey B, Bodey B Jr, Siegel SE, Kaiser HE (2000) Failure of cancer vaccines: the significant limitations of this approach to immunotherapy. Anticancer Res 20:2665–2676

    PubMed  CAS  Google Scholar 

  2. Hsueh EC, Essner R, Foshag LJ, Ollila DW, Gammon G, O’Day SJ, Boasberg PD, Stern SL, Ye X, Morton DL (2002) Prolonged survival after complete resection of disseminated melanoma and active immunotherapy with a therapeutic cancer vaccine. J Clin Oncol 20:4549–4554

    Article  PubMed  CAS  Google Scholar 

  3. Walker EB, Disis ML (2003) Monitoring immune responses in cancer patients receiving tumor vaccines. Int Rev Immunol 22:283–319

    Article  PubMed  CAS  Google Scholar 

  4. Romero P, Cerottini JC, Speiser DE (2004) Monitoring tumor antigen specific T-cell responses in cancer patients and phase I clinical trials of peptide-based vaccination. Cancer Immunol Immunother 53:249–255

    Article  PubMed  Google Scholar 

  5. Baars A, Claessen AM, van den Eertwegh AJ, Gall HE, Stam AG, Meijer S, Giaccone G, Meijer CJ, Scheper RJ, Wagstaff J, Vermorken JB, Pinedo HM (2000) Skin tests predict survival after autologous tumor cell vaccination in metastatic melanoma: experience in 81 patients. Ann Oncol 11:965–970

    Article  PubMed  CAS  Google Scholar 

  6. Bakker AB, Schreurs MW, Tafazzul G, de Boer AJ, Kawakami Y, Adema GJ, Figdor CG (1995) Identification of a novel peptide derived from the melanocyte-specific gp100 antigen as the dominant epitope recognized by an HLA-A2.1-restricted anti-melanoma CTL line. Int J Cancer 62:97–102

    Article  PubMed  CAS  Google Scholar 

  7. Kawakami Y, Eliyahu S, Sakaguchi K, Robbins PF, Rivoltini L, Yannelli JR, Appella E, Rosenberg SA (1994) Identification of the immunodominant peptides of the MART-1 human melanoma antigen recognized by the majority of HLA-A2-restricted tumor infiltrating lymphocytes. J Exp Med 180:347–352

    Article  PubMed  CAS  Google Scholar 

  8. Kawakami Y, Eliyahu S, Jennings C, Sakaguchi K, Kang X, Southwood S, Robbins PF, Sette A, Appella E, Rosenberg SA (1995) Recognition of multiple epitopes in the human melanoma antigen gp100 by tumor-infiltrating T lymphocytes associated with in vivo tumor regression. J Immunol 154:3961–3968

    PubMed  CAS  Google Scholar 

  9. Kawakami Y, Dang N, Wang X, Tupesis J, Robbins PF, Wang RF, Wunderlich JR, Yannelli JR, Rosenberg SA (2000) Recognition of shared melanoma antigens in association with major HLA-A alleles by tumor infiltrating T lymphocytes from 123 patients with melanoma. J Immunother 23:17–27

    Article  PubMed  CAS  Google Scholar 

  10. Skipper JC, Kittlesen DJ, Hendrickson RC, Deacon DD, Harthun NL, Wagner SN, Hunt DF, Engelhard VH, Slingluff CL Jr (1996) Shared epitopes for HLA-A3-restricted melanoma-reactive human CTL include a naturally processed epitope from Pmel-17/gp100. J Immunol 157:5027–5033

    PubMed  CAS  Google Scholar 

  11. Wolfel T, Van Pel A, Brichard V, Schneider J, Seliger B, Meyer zum Buschenfelde KH, Boon T (1994) Two tyrosinase nonapeptides recognized on HLA-A2 melanomas by autologous cytolytic T lymphocytes. Eur J Immunol 24:759–764

    Article  PubMed  CAS  Google Scholar 

  12. Zarour H, De Smet C, Lehmann F, Marchand M, Lethe B, Romero P, Boon T, Renauld JC (1996) The majority of autologous cytolytic T-lymphocyte clones derived from peripheral blood lymphocytes of a melanoma patient recognize an antigenic peptide derived from gene Pmel17/gp100. J Invest Dermatol 107:63–67

    Article  PubMed  CAS  Google Scholar 

  13. Anichini A, Molla A, Mortarini R, Tragni G, Bersani I, Di Nicola M, Gianni AM, Pilotti S, Dunbar R, Cerundolo V, Parmiani G (1999) An expanded peripheral T cell population to a cytotoxic T lymphocyte (CTL)-defined, melanocyte-specific antigen in metastatic melanoma patients impacts on generation of peptide-specific CTLs but does not overcome tumor escape from immune surveillance in metastatic lesions. J Exp Med 190:651–667

    Article  PubMed  CAS  Google Scholar 

  14. Dunbar PR, Smith CL, Chao D, Salio M, Shepherd D, Mirza F, Lipp M, Lanzavecchia A, Sallusto F, Evans A, Russell-Jones R, Harris AL, Cerundolo V (2000) A shift in the phenotype of melan-A-specific CTL identifies melanoma patients with an active tumor-specific immune response. J Immunol 165:6644–6652

    PubMed  CAS  Google Scholar 

  15. Zippelius A, Batard P, Rubio-Godoy V, Bioley G, Lienard D, Lejeune F, Rimoldi D, Guillaume P, Meidenbauer N, Mackensen A, Rufer N, Lubenow N, Speiser D, Cerottini JC, Romero P, Pittet MJ (2004) Effector function of human tumor-specific CD8 T cells in melanoma lesions: a state of local functional tolerance. Cancer Res 64:2865–2873

    Article  PubMed  CAS  Google Scholar 

  16. van Oijen M, Bins A, Elias S, Sein J, Weder P, de Gast GC, Mallo H, Gallee M, van Tinteren H, Schumacher TN, Haanen JB (2004) On the role of melanoma-specific CD8+ T cell immunity in disease progression of advanced-stage melanoma patients. Clin Cancer Res 10:4754–4760

    Google Scholar 

  17. 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  PubMed  CAS  Google Scholar 

  18. Valmori D, Fonteneau JF, Lizana CM, Gervois N, Lienard D, Rimoldi D, Jongeneel V, Jotereau F, Cerottini JC, Romero P (1998) Enhanced generation of specific tumor-reactive CTL in vitro by selected Melan-A/MART-1 immunodominant peptide analogues. J Immunol 160:1750–1758

    PubMed  CAS  Google Scholar 

  19. Skipper JC, Hendrickson RC, Gulden PH, Brichard V, Van Pel A, Chen Y, Shabanowitz J, Wolfel T, Slingluff CL Jr, Boon T, Hunt DF, Engelhard VH (1996) An HLA-A2-restricted tyrosinase antigen on melanoma cells results from posttranslational modification and suggests a novel pathway for processing of membrane proteins. J Exp Med 183:527–534

    Article  PubMed  CAS  Google Scholar 

  20. Mosse CA, Meadows L, Luckey CJ, Kittlesen DJ, Huczko EL, Slingluff CL, Shabanowitz J, Hunt DF, Engelhard VH (1998) The class I antigen-processing pathway for the membrane protein tyrosinase involves translation in the endoplasmic reticulum and processing in the cytosol. J Exp Med 187:37–48

    Article  PubMed  CAS  Google Scholar 

  21. Chaux P, Luiten R, Demotte N, Vantomme V, Stroobant V, Traversari C, Russo V, Schultz E, Cornelis GR, Boon T, van der Bruggen P (1999) Identification of five MAGE-A1 epitopes recognized by cytolytic T lymphocytes obtained by in vitro stimulation with dendritic cells transduced with MAGE-A1. J Immunol 163:2928–2936

    PubMed  CAS  Google Scholar 

  22. Maeurer MJ, Necker A, Salter RD, Castelli C, Hohn H, Karbach J, Freitag K, Neukirch C, Knuth A, Jager E (2002) Improved detection of melanoma antigen-specific T cells expressing low or high levels of CD8 by HLA-A2 tetramers presenting a Melan-A/Mart-1 peptide analogue. Int J Cancer 97:64–71

    Article  PubMed  CAS  Google Scholar 

  23. Whelan JA, Dunbar PR, Price DA, Purbhoo MA, Lechner F, Ogg GS, Griffiths G, Phillips RE, Cerundolo V, Sewell AK (1999) Specificity of CTL interactions with peptide-MHC class I tetrameric complexes is temperature dependent. J Immunol 163:4342–4348

    PubMed  CAS  Google Scholar 

  24. Schumacher K, Haensch W, Roefzaad C, Schlag PM (2001) Prognostic significance of activated CD8(+) T cell infiltrations within esophageal carcinomas. Cancer Res 61:3932–3936

    PubMed  CAS  Google Scholar 

  25. Vesalainen S, Lipponen P, Talja M, Syrjanen K (1994) Histological grade, perineural infiltration, tumour-infiltrating lymphocytes and apoptosis as determinants of long-term prognosis in prostatic adenocarcinoma. Eur J Cancer 30A:1797–1803

    Article  Google Scholar 

  26. Naito Y, Saito K, Shiiba K, Ohuchi A, Saigenji K, Nagura H, Ohtani H (1998) CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 58:3491–3494

    PubMed  CAS  Google Scholar 

  27. Nakano O, Sato M, Naito Y, Suzuki K, Orikasa S, Aizawa M, Suzuki Y, Shintaku I, Nagura H, Ohtani H (2001) Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity. Cancer Res 61:5132–5136

    PubMed  CAS  Google Scholar 

  28. Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN, Rubin SC, Coukos G (2003) Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348:203–213

    Article  PubMed  CAS  Google Scholar 

  29. Marrogi AJ, Munshi A, Merogi AJ, Ohadike Y, El-Habashi A, Marrogi OL, Freeman SM (1997) Study of tumor infiltrating lymphocytes and transforming growth factor-beta as prognostic factors in breast carcinoma. Int J Cancer 74:492–501

    Article  PubMed  CAS  Google Scholar 

  30. Clemente CG, Mihm MC Jr, Bufalino R, Zurrida S, Collini P, Cascinelli N (1996) Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer 77:1303–1310

    Article  PubMed  CAS  Google Scholar 

  31. Romero P, Dunbar PR, Valmori D, Pittet M, Ogg GS, Rimoldi D, Chen JL, Lienard D, Cerottini JC, Cerundolo V (1998) Ex vivo staining of metastatic lymph nodes by class I major histocompatibility complex tetramers reveals high numbers of antigen-experienced tumor-specific cytolytic T lymphocytes. J Exp Med 188:1641–1650

    Article  PubMed  CAS  Google Scholar 

  32. Yamshchikov G, Thompson L, Ross WG, Galavotti H, Aquila W, Deacon D, Caldwell J, Patterson JW, Hunt DF, Slingluff CL Jr (2001) Analysis of a natural immune response against tumor antigens in a melanoma survivor: lessons applicable to clinical trial evaluations. Clin Cancer Res 7:909s–16s

    PubMed  CAS  Google Scholar 

  33. Waanders GA, Rimoldi D, Lienard D, Carrel S, Lejeune F, Dietrich PY, Cerottini JC, Romero P (1997) Melanoma-reactive human cytotoxic T lymphocytes derived from skin biopsies of delayed-type hypersensitivity reactions induced by injection of an autologous melanoma cell line. Clin Cancer Res 3:685–696

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066, Amsterdam, The Netherlands

    J. B. A. G. Haanen, R. Gomez, P. Weder & M. Smits

  2. Department of Medical Oncology, Vrije Universiteit Medical Center, De Boelelaan 1117, Amsterdam, The Netherlands

    A. Baars, T. D. de Gruijl & A. J. M. van den Eertwegh

  3. Department of Pathology, Vrije Universiteit Medical Center, De Boelelaan 1117, Amsterdam, The Netherlands

    B. M. E. von Blomberg, E. Bloemena & R. J. Scheper

  4. Department of Immunopathology, Sanquin Research at CLB, Plesmanlaan 125, 1066, Amsterdam, The Netherlands

    S. M. van Ham

  5.  , Vrije Universiteit Cancer Center, P.O.Box 7057, 1007, Amsterdam, The Netherlands

    H. M. Pinedo

Authors
  1. J. B. A. G. Haanen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Baars
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. Gomez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P. Weder
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Smits
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T. D. de Gruijl
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B. M. E. von Blomberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. E. Bloemena
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. R. J. Scheper
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S. M. van Ham
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. H. M. Pinedo
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. A. J. M. van den Eertwegh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. J. M. van den Eertwegh.

Additional information

J.B.A.G. Haanen and A. Baars contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Haanen, J.B.A.G., Baars, A., Gomez, R. et al. Melanoma-specific tumor-infiltrating lymphocytes but not circulating melanoma-specific T cells may predict survival in resected advanced-stage melanoma patients. Cancer Immunol Immunother 55, 451–458 (2006). https://doi.org/10.1007/s00262-005-0018-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-005-0018-5

Keywords

Search

Navigation