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01.07.2013 | Original Article

Ex vivo analysis of pancreatic cancer-infiltrating T lymphocytes reveals that ENO-specific Tregs accumulate in tumor tissue and inhibit Th1/Th17 effector cell functions

verfasst von: Amedeo Amedei, Elena Niccolai, Marisa Benagiano, Chiara Della Bella, Fabio Cianchi, Paolo Bechi, Antonio Taddei, Lapo Bencini, Marco Farsi, Paola Cappello, Domenico Prisco, Francesco Novelli, Mario Milco D’Elios

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 7/2013

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Abstract

Pancreatic cancer (PC) is an aggressive disease with dismal prognosis. Surgical resection is the recommended treatment for long-term survival, but patients with resectable PC are in the minority (with a 5-year survival rate of 20 %). Therefore, development of novel therapeutic strategies, such as anti-PC immunotherapy, is crucial. α-Enolase (ENO1) is an enzyme expressed on the surface of pancreatic cancer cells and is able to promote cell migration and cancer metastasis. The capacity of ENO1 to induce an immune response in PC patients renders it a true tumor-associated antigen. In this study, we characterized the effector functions of ENO1-specific T cells isolated from PC patients, and we specifically evaluated the successful role of intra-tumoral T helper 17 (Th17) cells and the inhibitory role of regulatory T (Tregs) cells in respectively promoting or reducing the cancer-specific immune response. In this ex vivo study, we have demonstrated, for the first time, that ENO1-specific Th17 cells have a specific anti-cancer effector function in PC patients, and that there are decreased levels of these cells in cancer compared to healthy mucosa. Conversely, there are elevated levels of ENO1-specific Tregs in PC patients which lead to inhibition of the antigen-specific effector T cells, thus highlighting a possible role in promoting PC progression. These results may be relevant for the design of novel immunotherapeutic strategies in pancreatic cancer.

Hidalgo M (2010) Pancreatic cancer. N Engl J Med 362:1605–1617PubMedCrossRef

Goonetilleke KS, Siriwardena AK (2007) Nationwide questionnaire survey of the contemporary surgical management of pancreatic cancer in the United Kingdom & Ireland. Int J Surg 5:147–151PubMedCrossRef

Moon HJ, An JY, Heo JS, Choi SH, Joh JW, Kim YI (2006) Predicting survival after surgical resection for pancreatic ductal adenocarcinoma. Pancreas 32:37–43PubMedCrossRef

Laheru D, Lutz E, Burke J, Biedrzycki B, Solt S, Onners B, Tartakovsky I, Nemunaitis J, Le D, Sugar E, Hege K, Jaffee E (2008) Allogeneic granulocyte macrophage colony-stimulating factor-secreting tumor immunotherapy alone or in sequence with cyclophosphamide for metastatic pancreatic cancer: a pilot study of safety, feasibility, and immune activation. Clin Cancer Res 14:1455–1463PubMedCrossRef

Ramanathan RK, Lee KM, McKolanis J, Hitbold E, Schraut W, Moser AJ, Warnick E, Whiteside T, Osborne J, Kim H, Day R, Troetschel M, Finn OJ (2005) Phase I study of a MUC1 vaccine composed of different doses of MUC1 peptide with SB-AS2 adjuvant in resected and locally advanced pancreatic cancer. Cancer Immunol Immunother 54:254–264PubMedCrossRef

Jung S, Schluesener HJ (1991) Human T lymphocytes recognize a peptide of single point-mutated, oncogenic ras proteins. J Exp Med 173:273–276PubMedCrossRef

Nakatsura T, Senju S, Ito M, Nishimura Y, Itoh K (2002) Cellular and humoral immune responses to a human pancreatic cancer antigen, coactosin-like protein, originally defined by the SEREX method. Eur J Immunol 32:826–836PubMedCrossRef

Wobser M, Keikavoussi P, Kunzmann V, Weininger M, Andersen MH, Becker JC (2006) Complete remission of liver metastasis of pancreatic cancer under vaccination with a HLA-A2 restricted peptide derived from the universal tumor antigen survivin. Cancer Immunol Immunother 55:1294–1298PubMedCrossRef

Suso EM, Dueland S, Rasmussen AM, Vetrhus T, Aamdal S, Kvalheim G, Gaudernack G (2011) hTERT mRNA dendritic cell vaccination: complete response in a pancreatic cancer patient associated with response against several hTERT epitopes. Cancer Immunol Immunother 60:809–818PubMedCrossRef

10.

Cappello P, Tomaino B, Chiarle R, Ceruti P, Novarino A, Castagnoli C, Migliorini P, Perconti G, Giallongo A, Milella M, Monsurrò V, Barbi S et al (2009) An integrated humoral and cellular response is elicited in pancreatic cancer by alpha-enolase, a novel pancreatic ductal adenocarcinoma-associated antigen. Int J Cancer 125:639–648PubMedCrossRef

11.

Capello M, Ferri-Borgogno S, Cappello P, Novelli F (2011) α-Enolase: a promising therapeutic and diagnostic tumor target. FEBS J 278:1064–1074PubMedCrossRef

12.

Tomaino B, Cappello P, Capello M, Fredolini C, Sperduti I, Migliorini P, Salacone P, Novarino A, Giacobino A, Ciuffreda L, Alessio M, Nisticò P et al (2011) Circulating autoantibodies to phosphorylated alpha-enolase are a hallmark of pancreatic cancer. J Proteome Res 10:105–112PubMedCrossRef

13.

Cappello P, Rolla S, Chiarle R, Principe M, Cavallo F, Perconti G, Feo S, Giovarelli M, Novelli F (2013) Vaccination with ENO1 DNA prolongs survival of genetically engineered mice with pancreatic cancer. Gastroenterology. doi:10.1053/j.gastro.2013.01.020. [Epub ahead of print]

14.

Linehan DC, Goedegebuure PS (2005) CD25+ CD4+ regulatory T-cells in cancer. Immunol Res 32:155–168PubMedCrossRef

15.

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 169:2756–2761PubMed

16.

Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238PubMedCrossRef

17.

Sharma MD, Hou DY, Liu Y, Koni PA, Metz R, Chandler P, Mellor AL, He Y, Munn DH (2009) Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes. Blood 113:6102–6111PubMedCrossRef

18.

Bettelli E, Oukka M, Kuchroo VK (2007) T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol 8:345–350PubMedCrossRef

19.

Kryczek I, Wei S, Zou L, Altuwaijri S, Szeliga W, Kolls J, Chang A, Zou W (2007) Cutting edge: Th17 and regulatory T cell dynamics and the regulation by IL-2 in the tumor microenvironment. J Immunol 178:6730–6733PubMed

20.

Zhang B, Rong G, Wei H, Zhang M, Bi J, Ma L, Xue X, Wei G, Liu X, Fang G (2008) The prevalence of Th17 cells in patients with gastric cancer. Biochem Biophys Res Commun 374:533–537PubMedCrossRef

21.

Koyama K, Kagamu H, Miura S, Hiura T, Miyabayashi T, Itoh R, Kuriyama H, Tanaka H, Tanaka J, Yoshizawa H, Nakata K, Gejyo F (2008) Reciprocal CD4+ T-cell balance of effector CD62Llow CD4+ and CD62LhighCD25+ CD4+ regulatory T cells in small cell lung cancer reflects disease stage. Clin Cancer Res 14:6770–6779PubMedCrossRef

22.

Takahashi T, Kuniyasu Y, Toda M, Sakaguchi N, Itoh M, Iwata M, Shimizu J, Sakaguchi S (1998) Immunologic self-tolerance maintained by CD25+ CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. Int Immunol 10:1969–1980PubMedCrossRef

23.

Shevach EM (2001) Certified professionals: CD4(+)CD25(+) suppressor T cells. J Exp Med 193:F41–F46PubMedCrossRef

24.

Ikemoto T, Yamaguchi T, Morine Y, Imura S, Soejima Y, Fujii M, Maekawa Y, Yasutomo K, Shimada M (2006) Clinical roles of increased populations of Foxp3+ CD4+ T cells in peripheral blood from advanced pancreatic cancer patients. Pancreas 33:386–390PubMedCrossRef

25.

Viehl CT, Moore TT, Liyanage UK, Frey DM, Ehlers JP, Eberlein TJ, Goedegebuure PS, Linehan DC (2006) Depletion of CD4+ CD25+ regulatory T cells promotes a tumor-specific immune response in pancreas cancer bearing mice. Ann Surg Oncol 13:1252–1258PubMedCrossRef

26.

Warshaw AL, Fernández-del Castillo CN (1992) Pancreatic carcinoma. N Engl J Med 26:455–465CrossRef

27.

Amedei A, Della Bella C, Niccolai E, Stanflin N, Benagiano M, Duranti R, Del Prete G, Murphy TF, D’Elios MM (2009) Moraxella catarrhalis-specific Th1 cells in BAL fluids of chronic obstructive pulmonary disease patients. Int J Immunopathol Pharmacol 22:979–990PubMed

28.

Amedei A, Niccolai E, Della Bella C, Cianchi F, Trallori G, Benagiano M, Bencini L, Bernini M, Farsi M, Moretti R, Del Prete G, D’Elios MM (2009) Characterization of tumor antigen peptide-specific T cells isolated from the neoplastic tissue of patients with gastric adenocarcinoma. Cancer Immunol Immunother 58:1819–1830PubMedCrossRef

29.

Yu P, Haymaker CL, Divekar RD, Ellis JS, Hardaway J, Jain R, Tartar DM, Hoeman CM, Cascio JA, Ostermeier A, Zaghouani H (2008) Fetal exposure to high-avidity TCR ligand enhances expansion of peripheral T regulatory cells. J Immunol 181:73–80PubMed

30.

De Monte L, Reni M, Tassi E, Clavenna D, Papa I, Recalde H, Braga M, Di Carlo V, Doglioni C, Protti MP (2011) Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer. J Exp Med 208:469–478PubMedCrossRef

31.

von Bernstorff W, Voss M, Freichel S, Schmid A, Vogel I, Jöhnk C, Henne-Bruns D, Kremer B, Kalthoff H (2001) Systemic and local immunosuppression in pancreatic cancer patients. Clin Cancer Res 7:925s–932s

32.

Miyahara Y, Odunsi K, Chen W, Peng G, Matsuzaki J, Wang RF (2008) Generation and regulation of human CD4+ IL-17-producing T cells in ovarian cancer. Proc Natl Acad Sci USA 105:15505–15510PubMedCrossRef

33.

Su X, Ye J, Hsueh EC, Zhang Y, Hoft DF, Peng G (2010) Tumor microenvironments direct the recruitment and expansion of human Th17 cells. J Immunology 184:1630–1641CrossRef

34.

Kryczek I, Banerjee M, Cheng P, Vatan L, Szeliga W, Wei S, Huang E, Finlayson E, Simeone D, Welling TH, Chang A, Coukos G et al (2009) Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood 114:1141–1149PubMedCrossRef

35.

Horlock C, Stott B, Dyson PJ, Morishita M, Coombes RC, Savage P, Stebbing J (2009) The effects of trastuzumab on the CD4+ CD25+ FoxP3+ and CD4+ IL17A+ T-cell axis in patients with breast cancer. Br J Cancer 100:1061–1067PubMedCrossRef

36.

Benchetrit F, Ciree A, Vives V, Warnier G, Gey A, Sautès-Fridman C, Fossiez F, Haicheur N, Fridman WH, Tartour E (2002) Interleukin-17 inhibits tumor cell growth by means of a T-cell-dependent mechanism. Blood 99:2114–2121PubMedCrossRef

37.

Sfanos KS, Bruno TC, Maris CH, Xu L, Thoburn CJ, DeMarzo AM, Meeker AK, Isaacs WB, Drake CG (2008) Phenotypic analysis of prostate-infiltrating lymphocytes reveals TH17 and Treg skewing. Clin Cancer Res 4:3254–3261CrossRef

38.

Tartour E, Fossiez F, Joyeux I, Galinha A, Gey A, Claret E, Sastre-Garau X, Couturier J, Mosseri V, Vives V, Banchereau J, Fridman WH et al (1999) Interleukin 17, a T-cell-derived cytokine, promotes tumorigenicity of human cervical tumors in nude mice. Cancer Res 59:3698–3704PubMed

39.

Numasaki M, Fukushi J, Ono M, Narula SK, Zavodny PJ, Kudo T, Robbins PD, Tahara H, Lotze MT (2003) Interleukin-17 promotes angiogenesis and tumor growth. Blood 101:2620–2627PubMedCrossRef

40.

Alvarez E, Moga E, Barquinero J, Sierra J, Briones J (2009) Dendritic and tumor cell fusions transduced with adenovirus encoding CD40L eradicate B-cell lymphoma and induce a Th17-type response. Gene Ther 17:469–477PubMedCrossRef

41.

Kuang DM, Peng C, Zhao Q, Wu Y, Chen MS, Zheng L (2010) Activated monocytes in peritumoral stroma of hepatocellular carcinoma promote expansion of memory T helper 17 cells. Hepatology 51:154–164PubMedCrossRef

42.

Kyte JA, Trachsel S, Risberg B, Thor Straten P, Lislerud K, Gaudernack G (2009) Unconventional cytokine profiles and development of T cell memory in long-term survivors after cancer vaccination. Cancer Immunol Immunother 58:1609–1626PubMedCrossRef

43.

Martin-Orozco N, Muranski P, Chung Y, Yang XO, Yamazaki T, Lu S, Hwu P, Restifo NP, Overwijk WW, Dong C (2009) T helper 17 cells promote cytotoxic T cell activation in tumor immunity. Immunity 31:787–798PubMedCrossRef

44.

von Euw E, Chodon T, Attar N, Jalil J, Koya RC, Comin-Anduix B, Ribas A (2009) CTLA4 blockade increases Th17 cells in patients with metastatic melanoma. J Transl Med 7:35CrossRef

45.

Derhovanessian E, Adams V, Hähnel K, Groeger A, Pandha H, Ward S, Pawelec G (2009) Pretreatment frequency of circulating IL-17+ CD4+ T-cells, but not Tregs, correlates with clinical response to whole-cell vaccination in prostate cancer patients. Int J Cancer 125:1372–1379PubMedCrossRef

Titel: Ex vivo analysis of pancreatic cancer-infiltrating T lymphocytes reveals that ENO-specific Tregs accumulate in tumor tissue and inhibit Th1/Th17 effector cell functions
verfasst von: Amedeo Amedei
Elena Niccolai
Marisa Benagiano
Chiara Della Bella
Fabio Cianchi
Paolo Bechi
Antonio Taddei
Lapo Bencini
Marco Farsi
Paola Cappello
Domenico Prisco
Francesco Novelli
Mario Milco D’Elios
Publikationsdatum: 01.07.2013
Verlag: Springer-Verlag
Erschienen in: Cancer Immunology, Immunotherapy / Ausgabe 7/2013
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-013-1429-3

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Ex vivo analysis of pancreatic cancer-infiltrating T lymphocytes reveals that ENO-specific Tregs accumulate in tumor tissue and inhibit Th1/Th17 effector cell functions

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