Cancer Immunology, Immunotherapy

, Volume 58, Issue 11, pp 1819–1830 | Cite as

Characterization of tumor antigen peptide-specific T cells isolated from the neoplastic tissue of patients with gastric adenocarcinoma

  • Amedeo Amedei
  • Elena Niccolai
  • Chiara Della Bella
  • Fabio Cianchi
  • Giacomo Trallori
  • Marisa Benagiano
  • Lapo Bencini
  • Marco Bernini
  • Marco Farsi
  • Renato Moretti
  • Gianfranco Del Prete
  • Mario Milco D’Elios
Original article

Abstract

Gastric cancer is a significant cause of morbidity and mortality worldwide. Surgical resection remains the primary curative treatment for gastric adenocarcinoma, but the poor (15–35%) survival rate at 5 years has prompted many studies for new therapeutic strategies, such as specific immunotherapy. The aim of this study was to analyze the functional properties of the T cell response to different antigen peptides related to gastric cancer in patients with gastric adenocarcinoma. To this purpose, we have cloned and characterized tumor-infiltrating T cells (TILs) isolated from the neoplastic gastric tissue samples. A T cell response specific to different peptides of gastric cancer antigens tested was documented in 17 out of 20 patients, selected for their HLA-A02 and/or -A24 alleles. Most of the cancer peptide-specific TILs expressed a Th1/Tc1 profile and cytotoxic activity against target cells. The effector functions of cancer peptide-specific T cells obtained from the peripheral blood of the same patients were also studied. The majority of peripheral blood peptide-specific T cells also expressed the Th1/Tc1 functional profile. In conclusion, in most of the patients with gastric adenocarcinoma, a specific type-1 T cell response to gastric cancer antigens was detectable and would have the potential of hamper tumor cell growth. However, in order to get tumor cell killing in vivo, the activity and the number of cancer peptide-specific Th1/Tc1 cells probably need to be enhanced by vaccination with the appropriate cancer antigenic peptides or by injection of the autologus tumor peptide-specific T cells expanded in vitro.

Keywords

Gastric adenocarcinoma Tumor-infiltrating lymphocytes Th1/Tc1 Gastric cancer antigen-associated peptides 

Abbreviations

GCAA

Gastric cancer antigen-associated peptides

PBMC

Peripheral blood mononuclear cells

Th1 and Th0

Type 1 and type 0 helper CD4 + T cells

Tc1 and Tc0

Type 1 and type 0 cytotoxic CD8 + T cells

TILs

Tumor-infiltrating lymphocytes

Notes

Acknowledgments

We wish to thank Istituto Superiore di Sanità, Ente Cassa di Risparmio di Firenze and Italian Ministry of University and Research for their support of our studies.

References

  1. 1.
    Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ (2006) MAGIC trial participants perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355:11–20PubMedCrossRefGoogle Scholar
  2. 2.
    D’Elios MM, Manghetti M, Almerigogna F, Amedei A, Costa F, Burroni D, Baldari CT, Romagnani S, Telford JL, Del Prete G (1997) Different cytokine profile and antigen-specificity repertoire in Helicobacter pylori-specific T cell clones from the antrum of chronic gastritis patients with or without peptic ulcer. Eur J Immunol 27:1751–1755PubMedCrossRefGoogle Scholar
  3. 3.
    D’Elios MM, Amedei A, Manghetti M, Costa M, Baldari CT, Quazi AS, Telford JL, Romagnani S, Del Prete G (1999) Impaired T-cell regulation of B-cell growth in Helicobacter pylori-related gastric low-grade MALT lymphoma. Gastroenterology 117:1105–1112PubMedCrossRefGoogle Scholar
  4. 4.
    D’Elios MM, Bergman MP, Azzurri A, Amedei A, Benagiano M, De Pont JJ, Cianchi F, Vandenbroucke-Grauls CM, Romagnani S, Appelmelk BJ, Del Prete G (2001) H(+), K(+)-atpase (proton pump) is the target autoantigen of Th1-type cytotoxic T cells in autoimmune gastritis. Gastroenterology 120:377–386PubMedCrossRefGoogle Scholar
  5. 5.
    Darrow TL, Abdel-Wahab Z, Quinn-Allen MA, Seigler HF (1996) Recognition and lysis of human melanoma by a CD3+, CD4+, CD8- T-cell clone restricted by HLA-A2. Cell Immunol 172:52–59PubMedCrossRefGoogle Scholar
  6. 6.
    Del Prete G, De Carli M, Ricci M, Romagnani S (1991) Helper activity for immunoglobulin synthesis of T helper type I (Thl) and Th2 human T cell clones: the help of Thl clones is limited by their cytolytic capacity. J Exp Med I74:809–813CrossRefGoogle Scholar
  7. 7.
    Del Prete G, De Carli M, Mastromauro C, Biagiotti R, Macchia D, Falagiani P, Ricci M, Romagnani S (1991) Purified protein derivative of Mycobacterium tuberculosis and excretory–secretory antigen(s) of Toxocara canis expand in vitro human T cells with stable and opposite (type 1 T helper or type 2 T helper) profile of cytokine production. J Clin Invest 83:346–350CrossRefGoogle Scholar
  8. 8.
    Del Prete G, De Carli M, D’Elios MM, Maestrelli P, Ricci M, Fabbri L, Romagnani S (1993) Allergen exposure induces the activation of allergen-specific Th2 cells in the airway mucosa of patients with allergic respiratory disorders. Eur J Immunol 23:1445–1449PubMedCrossRefGoogle Scholar
  9. 9.
    Elkord E, Hawkins RE, Stern PL (2008) Immunotherapy for gastrointestinal cancer: current status and strategies for improving efficacy. Expert Opin Biol Ther 8:385–395PubMedCrossRefGoogle Scholar
  10. 10.
    El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, Herrera J, Lissowska J, Yuan CC, Rothman N, Lanyon G, Martin M, Fraumeni JF Jr, Rabkin CS (2000) Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 404:398–402PubMedCrossRefGoogle Scholar
  11. 11.
    Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P (2007) Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 18:581–592PubMedCrossRefGoogle Scholar
  12. 12.
    Ge Q, Holler PD, Mahajan VS, Nuygen T, Eisen HN, Chen J (2006) Development of CD4+ T cells expressing a nominally MHC class I-restricted T cell receptor by two different mechanisms. Proc Natl Acad Sci USA 103:1822–1827PubMedCrossRefGoogle Scholar
  13. 13.
    Gomi S, Nakao M, Niiya F, Imamura Y, Kawano K, Nishizaka S, Hayashi A, Sobao Y, Oizumi K, Itoh K (1999) A cyclophilin B gene encodes antigenic epitopes recognized by HLA-A24-restricted and tumor-specific cytotoxic T lymphocytes. J Immunol 163:4994–5004PubMedGoogle Scholar
  14. 14.
    RC IA (1994) IARC monograph on the evaluation of carcinogenic risks to humans: Schistosomes, Liver Flukes and Helicobacter pylori, vol 16. IARC, LyonGoogle Scholar
  15. 15.
    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 9:4404–4408PubMedGoogle Scholar
  16. 16.
    Imai N, Harashima N, Ito M, Miyagi Y, Harada M, Yamada A, Itoh K (2001) Identification of Lck-derived peptides capable of inducing HLA-A2-restricted and tumor-specific CTLs in cancer patients with distant metastases. Int J Cancer 94:237–242PubMedCrossRefGoogle Scholar
  17. 17.
    Ito M, Shichijo S, Tsuda N, Ochi M, Harashima N, Saito N, Itoh K (2001) Molecular basis of T cell-mediated recognition of pancreatic cancer cells. Cancer Res 61:2038–2046PubMedGoogle Scholar
  18. 18.
    Kaper T, Looger LL, Takanaga H, Platten M, Steinman L, Frommer WB (2007) Nanosensor detection of an immunoregulatory tryptophan influx/kynurenine efflux cycle. PLoS Biol 5:e257PubMedCrossRefGoogle Scholar
  19. 19.
    Kawano K, Gomi S, Tanaka K, Tsuda N, Kamura T, Itoh K, Yamada A (2000) Identification of a new endoplasmic reticulum-resident protein recognized by HLA-A24-restricted tumor infiltrating lymphocytes of lung cancer. Cancer Res 60:3550–3558PubMedGoogle Scholar
  20. 20.
    Kelley JR, John M (2003) Duggan Gastric cancer epidemiology and risk factors. J Clin Epidemiol 56:1–9PubMedCrossRefGoogle Scholar
  21. 21.
    Kono K, Takahashi A, Sugai H, Fujii H, Choudhury AR, Kiessling R, Matsumoto Y (2002) Dendritic cells pulsed with HER-2/neu-derived peptides can induce specific T-cell responses in patients with gastric cancer. Clin Cancer Res 8:3394–3400PubMedGoogle Scholar
  22. 22.
    Kroemer G, Pouyssegur J (2008) Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell 13:472–482PubMedCrossRefGoogle Scholar
  23. 23.
    Liakakos T, Roukos DH (2008) More controversy than ever-challenges and promises towards personalized treatment of gastric cancer. Ann Surg Oncol 15:956–960PubMedCrossRefGoogle Scholar
  24. 24.
    Marchall BJ, Windsor HM (2005) The relation of Helicobacter pylori to gastric adenocarcinoma and lymphoma: pathophysiology, epidemiology, screening, clinical presentation, treatment, and prevention. Med Clin North Am 89:313–344CrossRefGoogle Scholar
  25. 25.
    Mayne ST, Risch HA, Dubrow R, Chow WH, Gammon MD, Vaughan TL, Farrow DC, Schoenberg JB, Stanford JL, Ahsan H, West AB, Rotterdam H, Blot WJ, Fraumeni JF Jr (2001) Nutrient intake and risk of subtypes of esophageal and gastric cancer. Cancer Epidemiol Biomarkers Prev 10:1055–1062PubMedGoogle Scholar
  26. 26.
    Minami T, Matsueda S, Takedatsu H, Tanaka M, Noguchi M, Uemura H, Itoh K, Harada M (2007) Identification of SART3-derived peptides having the potential to induce cancer-reactive cytotoxic T lymphocytes from prostate cancer patients with HLA-A3 supertype alleles. Cancer Immunol Immunother 56:689–698PubMedCrossRefGoogle Scholar
  27. 27.
    Mine T, Gouhara R, Hida N, Imai N, Azuma K, Rikimaru T, Katagiri K, Nishikori M, Sukehiro A, Nakagawa M, Yamada A, Aizawa H, Shirouzu K, Itoh K, Yamana H (2003) Immunological evaluation of CTL precursor-oriented vaccines for advanced lung cancer patients. Cancer Sci 94:548–556PubMedCrossRefGoogle Scholar
  28. 28.
    Mine T, Sato Y, Noguchi M, Sasatomi T, Gouhara R, Tsuda N, Tanaka S, Shomura H, Katagiri K, Rikimaru T, Shichijo S, Kamura T, Hashimoto T, Shirouzu K, Yamada A, Todo S, Itoh K, Yamana H (2004) Humoral responses to peptides correlate with overall survival in advanced cancer patients vaccinated with peptides based on pre-existing, peptide-specific cellular responses. Clin Cancer Res 10:929–937PubMedCrossRefGoogle Scholar
  29. 29.
    Mochizuki K, Sato Y, Tsuda N, Shomura H, Sakamoto M, Matsuura K, Ushijima K, Maeda Y, Katagiri K, Yamada A, Todo S, Kamura T, Harada M, Itoh K (2004) Immunological evaluation of vaccination with pre-designated peptides frequently selected as vaccine candidates in an individualized peptide vaccination regimen. Int J Oncol 25:121–131PubMedGoogle Scholar
  30. 30.
    Moretta A, Pantaleo G, Moretta L, Cerottini JC, Mingari MC (1983) Direct demonstration of the clonogenic potential of every human peripheral blood T cell: clonal analysis of HLA-DR expression and cytolytic activity. J Exp Med 157:743–751PubMedCrossRefGoogle Scholar
  31. 31.
    Muller AJ, DuHadaway JB, Donover PS, Sutanto-Ward E, Prendergast GC (2005) Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat Med 11:312–319PubMedCrossRefGoogle Scholar
  32. 32.
    Nagaraj S, Gabrilovich DI (2008) Tumor escape mechanism governed by myeloid-derived suppressor cells. Cancer Res 68:2561–2563PubMedCrossRefGoogle Scholar
  33. 33.
    Naito M, Komohara Y, Ishihara Y, Noguchi M, Yamashita Y, Shirakusa T, Yamada A, Itoh K, Harada M (2007) Identification of Lck-derived peptides applicable to anti-cancer vaccine for patients with human leukocyte antigen-A3 supertype alleles. Br J Cancer 97:1648–1654PubMedCrossRefGoogle Scholar
  34. 34.
    Nakao M, Shichijo S, Imaizumi T, Inoue Y, Matsunaga K, Yamada A, Kikuchi M, Tsuda N, Ohta K, Takamori S, Yamana H, Fujita H, Itoh K (2000) Identification of a gene coding for a new squamous cell carcinoma antigen recognized by the CTL. J Immunol 164:2565–2574PubMedGoogle Scholar
  35. 35.
    Naumann M, Crabtree JE (2004) Helicobacter pylori-induced epithelial cell signaling in gastric carcinogenesis. Trends Microbiol 12:29–36PubMedCrossRefGoogle Scholar
  36. 36.
    Niiya F, Nishizaka S, Matsunaga K, Koufuji K, Mori M, Katai H, Yamana H, Itoh K (2000) Expression of SART3 tumor-rejection antigen in gastric cancers. Jpn J Cancer Res 91:337–342PubMedGoogle Scholar
  37. 37.
    Nishimura MI, Avichezer D, Custer MC, Lee CS, Chen C, Parkhurst MR, Diamond RA, Robbins PF, Schwartzentruber DJ, Rosenberg SA (1999) MHC class I-restricted recognition of a melanoma antigen by a human CD4+ tumor infiltrating lymphocyte. Cancer Res 59:6230–6238PubMedGoogle Scholar
  38. 38.
    Nishizaka S, Gomi S, Harada K, Oizumi K, Itoh K, Shichijo S (2000) A new tumor- rejection antigen recognized by cytotoxic T lymphocytes infiltrating into a lung adenocarcinoma. Cancer Res 60:4830–4837PubMedGoogle Scholar
  39. 39.
    Ocean AJ, Schnoll-Sussman F, Keresztes R, Chen X, Holloway S, Matthews N, Christos P, Mazumdar M, Wright J, Wadler S (2006) Phase II study of PS-341 (bortezomib) with or without irinotecan in patients (pts) with advanced gastric adenocarcinomas (AGA). J Clin Oncol (20 June Supplement):14040Google Scholar
  40. 40.
    Ohyauchi M, Imatani A, Yonechi M, Asano N, Miura A, Iijima K, Koike T, Sekine H, Ohara S, Shimosegawa T (2005) The polymorphism interleukin 8-251 A/T influences the susceptibility of Helicobacter pylori related gastric diseases in the Japanese population. Gut 54:330–335PubMedCrossRefGoogle Scholar
  41. 41.
    Peek RM, Blaser MJ (2002) Helicobacter pylori and gastrointestinal adenocarcinomas. Nat Rev Cancer 2:28–37PubMedCrossRefGoogle Scholar
  42. 42.
    Rocco A, Nardone G (2007) Diet, H pylori infection and gastric cancer: evidence and controversies. World J Gastroenterol 13:2901–2912PubMedGoogle Scholar
  43. 43.
    Roukos DH, Kappas AM (2005) Perspectives in the treatment of gastric cancer. Nat Clin Pract Oncol 2:98–107PubMedCrossRefGoogle Scholar
  44. 44.
    Sato Y, Shomura H, Maeda Y, Mine T, Une Y, Akasaka Y, Kondo M, Takahashi S, Shinohara T, Katagiri K, Sato M, Okada S, Matsui K, Yamada A, Yamana H, Itoh K, Todo S (2003) Immunological evaluation of peptide vaccination for patients with gastric cancer based on pre-existing cellular response to peptide. Cancer Sci 94:802–808PubMedCrossRefGoogle Scholar
  45. 45.
    Sato Y, Fujiwara T, Mine T, Shomura H, Homma S, Maeda Y, Tokunaga N, Ikeda Y, Ishihara Y, Yamada A, Tanaka N, Itoh K, Harada M, Todo S (2007) Immunological evaluation of personalized peptide vaccination in combination with a 5-fluorouracil derivative (TS-1) for advanced gastric or colorectal carcinoma patients. Cancer Sci 98:1113–1119PubMedCrossRefGoogle Scholar
  46. 46.
    Shah MA, Ramanathan RK, Ilson DH, Levnor A, D’Adamo D, O’Reilly E, Tse A, Trocola R, Schwartz L, Capanu M, Schwartz GK, Kelsen DP (2006) Multicenter phase II study of irinotecan, cisplatin, and bevacizumab in patients with metastatic gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol 24:5201–5206PubMedCrossRefGoogle Scholar
  47. 47.
    Shichijo S, Nakao M, Imai Y, Takasu H, Kawamoto M, Niiya F, Yang D, Toh Y, Yamana H, Itoh K (1998) A gene encoding antigenic peptides of human squamouscell carcinoma recognized by cytotoxic T lymphocytes. J Exp Med 187:277–288PubMedCrossRefGoogle Scholar
  48. 48.
    Somasundaram R, Robbins P, Moonka D, Loh E, Marincola F, Patel A, Guerry D, Herlyn D (2000) CD4(+), HLA class I-restricted, cytolytic T-lymphocyte clone against primary malignant melanoma cells. Int J Cancer 85:253–259PubMedGoogle Scholar
  49. 49.
    Vanhoefer U, Tewes M, Rojo F, Dirsch O, Schleucher N, Rosen O, Tillner J, Kovar A, Braun AH, Trarbach T, Seeber S, Harstrick A, Baselga J (2004) Phase I study of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with advanced solid tumors that express the epidermal growth factor receptor. J Clin Oncol 22:175–184PubMedCrossRefGoogle Scholar
  50. 50.
    Vergelli M, Hemmer B, Muraro PA, Tranquilli L, Biddison WE, Sarin A, McFarland HF, Martin R (1997) Human autoreactive CD4+ T cell clones use perforin- or Fas/Fas ligand-mediated pathways for target cell lysis. J Immunol 158:2756–2761PubMedGoogle Scholar
  51. 51.
    Yang D, Nakao M, Shichijo S, Sasatomi T, Takasu H, Matsumoto H, Mori K, Hayashi A, Yamana H, Shirouzu K, Itoh K (1999) Identification of a gene coding for a protein possessing shared tumor epitopes capable of inducing HLAA24-restricted cytotoxic T lymphocytes in cancer patients. Cancer Res 59:4056–4063PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Amedeo Amedei
    • 1
    • 2
  • Elena Niccolai
    • 1
    • 2
  • Chiara Della Bella
    • 1
    • 2
  • Fabio Cianchi
    • 3
  • Giacomo Trallori
    • 4
  • Marisa Benagiano
    • 1
    • 2
  • Lapo Bencini
    • 5
  • Marco Bernini
    • 5
  • Marco Farsi
    • 5
  • Renato Moretti
    • 5
  • Gianfranco Del Prete
    • 1
    • 2
  • Mario Milco D’Elios
    • 1
    • 2
  1. 1.Department of Internal MedicineUniversity of FlorenceFlorenceItaly
  2. 2.Department of BiomedicineAzienda Ospedaliera Universitaria Careggi (AOUC)FlorenceItaly
  3. 3.Department of Medical and Surgical Critical CareUniversity of FlorenceFlorenceItaly
  4. 4.Gastroenterology UnitAOUCFlorenceItaly
  5. 5.Division of General and Oncologic Surgery, Department of OncologyAOUCFlorenceItaly

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