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Immune responses to p53 in patients with cancer:enrichment in tetramer+ p53 peptide-specific T cells and regulatory T cells at tumor sites

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Abstract

Objective: A majority of human cancers, including head and neck cancer (HNC), “overexpress” p53. Although T cells specific for wild-type (wt) sequence p53 peptides are detectable in the peripheral blood of patients with HNC, it is unknown whether such T cells accumulate in tumor-involved tissues. Also, the localization of “regulatory” T cells (Treg) to tumor sites in HNC has not been investigated to date. Methods: Tumor infiltrating lymphocytes (TIL), tumor-involved or non-involved lymph node lymphocytes (LNL) and peripheral blood mononuclear cells (PBMC) were obtained from 24 HLA-A2.1+ patients with HNC. Using tetramers and four-color flow cytometry, the frequency of Treg and CD3+CD8+ T cells specific for wt p53 epitopes as well as their functional attributes were determined. Results: The CD3+CD8+ tetramer+ cell frequency was significantly higher (P<0.001) in TIL than autologous PBMC as was the percentage of CD4+CD25+ T cells (P<0.003). TIL were enriched in FOXp3+, GITR+ and CTLA-4+ Treg. CD8+ TIL had low Ζ expression and produced little IFN-γ after ex vivo stimulation relative to autologous PBMC or PBMC from NC. Conclusions: Anti-wt p53 epitope-specific T cells and Treg preferentially localize to tumor sites in patients with HNC. However, despite enrichment in tumor peptide-specific T cells, the effector cell population (CD3+CD8+) in TIL or PBMC was unresponsive to activation in the tumor microenvironment enriched in Treg.

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References

  1. Chikamatsu K, Nakano K, Storkus WJ, Appell E, Lotze MT, Whiteside TL, DeLeo AB (1999) Generation of anti-p53 cytotoxic T lymphocytes from human peripheral blood using autologous dendritic cells. Clin Cancer Res 5:1281

    Google Scholar 

  2. Curiel TJ, Coukos G, Zou L, Alvarez X, et al (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942

    Article  CAS  PubMed  Google Scholar 

  3. Elder EM, Whiteside TL (1992) Processing of tumors for vaccine and/or tumor infiltrating lymphocytes. In: Friedman H, Rose NR, deMacario EC, Fahey JL, Friedman H, Penn GM (Eds) Manual of clinical laboratory immunology, vol 123, 4th edn. American Society of Microbiology, Washington, p 817

  4. Gnjatic S, Cai Z, Viguier M, Chouaib S, Guillet J-G, Choppin J (1998) Accumulation of the p53 protein allows recognition by human CTL of a wild-type p53 epitope presented by breast carcinomas and melanomas. J Immunol 160:328

    CAS  PubMed  Google Scholar 

  5. Harris CC (1996) Structure and function of the p53 tumor suppressor gene: clues and rational cancer therapeutic strategies. J Natl Cancer Inst 88:1442

    Google Scholar 

  6. Herrin V, Behrens RJ, Achtar M, Monahan B, Bernstein S, Brent-Steele T, Whiteside T, Wieckowski E, Berzofsky J, Khleif SN (2003) Wild-type p53 peptide vaccine can generate a specific immune response in low burden ovarian adenocarcinoma. Abstr 678 Proc Am Soc Clin Oncol 22:169

    Google Scholar 

  7. Hoffmann TK, Nakano K, Elder E, Dworacki G, Finkelstein SD, Apella E, Whiteside TL, DeLeo AB (2000) Generation of T cells specific for the wild-type sequence p53264-272 peptide in cancer patients—implications for immunoselection of epitope-loss variants. J Immunol 165:5938

    CAS  PubMed  Google Scholar 

  8. Hoffman TK, Donnenberg AD, Finkelstein SD, Donnenberg VS, Friebe-Hoffmann F, Myers EN, Appella E, DeLeo AB, Whiteside TL (2002) Frequencies of tetramer+ T cells specific for the wild-type sequence p53264-272 peptide in the circulations of patients with head and neck cancer. Cancer Res 62:3521

    PubMed  Google Scholar 

  9. Hoffmann TK, Donnenberg V, Friebe-Hoffmann U, Meyer M, Rinaldo CR, DeLeo AB, Whiteside TL, and Donnenberg AD (2000) Competition of peptide-MHC class I tetrameric complexes with anti-CD3 provides evidence for specificity of peptide binding to the TCR complex. Cytometry 41:321

    Article  CAS  PubMed  Google Scholar 

  10. Hoffmann TK, Dworacki G, Meidenbauer N, Gooding W, Johnson JT, Whiteside TL (2002) Spontaneous apoptosis of circulating T lymphocytes in patients with head and neck cancer and its clinical importance. Clin Cancer Res 8:2553

    PubMed  Google Scholar 

  11. Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancers. Science 253:49

    CAS  PubMed  Google Scholar 

  12. Hollstein M, Shomer B, Greenblatt M, Soussi T, Hovig E, Montesano R, Harris CC (1996) Somatic point mutations in the p53 gene of human tumors and cell lines: updated compilation. Nucleic Acids Res 24:141

    Article  CAS  PubMed  Google Scholar 

  13. Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, Enk AH (2001) Identification and functional characterization of human CD4+CD25+ T cells with regulatory properties isolated from peripheral blood. J Exp Med 193:1285

    Article  CAS  PubMed  Google Scholar 

  14. Lee KM, Chuang E, Griffin M, et al (1998) Molecular basis of T cell inactivation by CTLA-4. Science 282:2263

    Article  CAS  PubMed  Google Scholar 

  15. Letessier E, Sacchi M, Johnson JT, Herberman RB, Whiteside TL (1990) The absence of lymphoid suppressor cells in tumor-involved lymph nodes of patients with head and neck cancer. Cell Immunol 130:446

    Article  CAS  PubMed  Google Scholar 

  16. Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G, Drebin JA, Strasberg SM, Eberlein TJ, Goedegebuure PS, Linehan DC (2002) Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 169:2756

    CAS  PubMed  Google Scholar 

  17. Marincola FM, Jaffee EM, Hicklin DJ, Ferrone S (2000) Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. Adv Immunol 74:181

    CAS  PubMed  Google Scholar 

  18. Ng WF, Duggan PJ, Ponchel F, Matarese G, Lombardi G, Edwards AD, Isaacs JD, Lechler RI (2001) Human CD4+CD25+ cells: a naturally occurring population of regulatory T cells. Blood 98:2736

    Article  CAS  PubMed  Google Scholar 

  19. Ramsdell F (2003) Foxp3 and natural regulatory T cells: key to a cell lineage? Immunity 19:165

    Article  CAS  PubMed  Google Scholar 

  20. Raybaud-Diogene H, Tetu B, Morency R, Fortin A, Monteil R (1996) p53 overexpression in head and neck squamous cell carcinoma: review of the literature. Eur J Cancer B Oral Oncol 32b:143

    Article  Google Scholar 

  21. Reichert TE, Strauss L, Wagner EM, Gooding W, Whiteside TL (2002) Signaling abnormalities and reduced proliferation of circulating and tumor-infiltrating lymphocytes in patients with oral carcinoma. Clin Cancer Res 8:3137

    PubMed  Google Scholar 

  22. Ronchetti S, Zollo O, Bruscoll S, Agostini M, Bianchini R, Nocentini G, Ayroldi E, Riccardi C (2004) GITR, a member of the TNF receptor superfamily, is costimulatory to mouse T lymphocyte subpopulations. Eur J Immunol 34:613

    Article  CAS  PubMed  Google Scholar 

  23. Schaefer C, Kim GG, Albers A, Hoermann K, Myers EN, Whiteside TL (2005) Characteristics of CD4+CD25+ regulatory T cells in the peripheral circulation of patients with head and neck cancer. Br J Cancer 92:913

    Article  CAS  PubMed  Google Scholar 

  24. Shimizu J, Yamazaki S, Sakaguchi S (1999) Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 163:5211

    PubMed  Google Scholar 

  25. Soussi T (1996) The humoral response to the tumor-suppressor gene-product p53 in human cancer: implications for the diagnosis and therapy. Immunol Today 17:354

    Article  CAS  PubMed  Google Scholar 

  26. Shevach EM (2004) Fatal attraction: tumors becon regulatory T cells. Nat Med 10:900

    Article  CAS  PubMed  Google Scholar 

  27. Stephens GL, McHugh RS, Whitters MJ, Young DA et al (2004) Engagement of glucocorticoid-induced TNFR family-related receptor on effector T cells by its ligand mediates resistance to suppression by CD4+CD25+ T cells. J Immunol 173:5008

    CAS  PubMed  Google Scholar 

  28. 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 52:599

    Article  PubMed  Google Scholar 

  29. Whiteside TL (2002) Tumor-induced death of immune cells: its mechanisms and consequences. Sem Cancer Biol 12:43

    Article  CAS  Google Scholar 

  30. Whiteside TL, Rabinowich H (1998) The role of Fas/FasL in immunosuppression induced by human tumors. Cancer Immunol Immunother 46:175

    Google Scholar 

  31. Wolf AM, Wolf D, Steurer M, Gasti G, Gunsilius E, Grubeck-loebenstein B (2003) Increase in regulatory T cells in the peripheral blood of cancer patients. Clin Cancer Res 9:606

    PubMed  Google Scholar 

  32. Woo EY, Chu CS, Goletz TJ, Schlienger K, Yeh H, Coukos G, Rubin SC, Kaiser LR, June CH (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 61:4766

    Google Scholar 

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Acknowledgements

This work has been supported in part by the NIH grants PO1-DE12321 (TLW), P60-DE13059 and The Stout Family Fund for Head and Neck Cancer Research at the Eye and Ear Foundation of Pittsburgh.

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Authors and Affiliations

  1. University of Pittsburgh Cancer Institute and Departments of Pathology (ABD, TLW), Immunology and Otolaryngology (RLF, TLW), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, 15213, USA

    Andreas E. Albers, Robert L. Ferris, Grace G. Kim, Kazuaki Chikamatsu, Albert B. DeLeo & Theresa L. Whiteside

  2. Research Pavilion at the Hillman Cancer Center, University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Suite 1.27, Pittsburgh, PA, 15213, USA

    Theresa L. Whiteside

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  1. Andreas E. Albers
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  2. Robert L. Ferris
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  3. Grace G. Kim
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  4. Kazuaki Chikamatsu
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  5. Albert B. DeLeo
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  6. Theresa L. Whiteside
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Correspondence to Theresa L. Whiteside.

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Albers, A.E., Ferris, R.L., Kim, G.G. et al. Immune responses to p53 in patients with cancer:enrichment in tetramer+ p53 peptide-specific T cells and regulatory T cells at tumor sites. Cancer Immunol Immunother 54, 1072–1081 (2005). https://doi.org/10.1007/s00262-005-0670-9

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  • DOI: https://doi.org/10.1007/s00262-005-0670-9

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