Peripheral ENO1-specific T cells mirror the intratumoral immune response and their presence is a potential prognostic factor for pancreatic adenocarcinoma

Niccolai,Elena; Cappello,Paola; Taddei,Antonio; Ricci,Federica; D'Elios,Mario Milco; Benagiano,Marisa; Bechi,Paolo; Bencini,Lapo; Ringressi,Maria Novella; Coratti,Andrea; Cianchi,Fabio; Bonello,Lisa; Di Celle,Paola Francia; Prisco,Domenico; Novelli,Francesco; Amedei,Amedeo

doi:10.3892/ijo.2016.3524

Peripheral ENO1-specific T cells mirror the intratumoral immune response and their presence is a potential prognostic factor for pancreatic adenocarcinoma

Authors:
- Elena Niccolai
- Paola Cappello
- Antonio Taddei
- Federica Ricci
- Mario Milco D'Elios
- Marisa Benagiano
- Paolo Bechi
- Lapo Bencini
- Maria Novella Ringressi
- Andrea Coratti
- Fabio Cianchi
- Lisa Bonello
- Paola Francia Di Celle
- Domenico Prisco
- Francesco Novelli
- Amedeo Amedei
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Affiliations: Department of Experimental and Clinical Medicine, University of Florence, and Department of Biomedicine, Azienda Ospedaliera Universitaria Careggi (AOUC), I-50134 Florence, Italy, Centre for Experimental Research and Medical Studies (CERMS), AOU City of Health and Science of Turin, and Department of Molecular Biotechnology and Health Sciences, University of Turin, I-10126 Turin, Italy, Department of Surgery and Translational Medicine, University of Florence, and Department of Biomedicine, Azienda Ospedaliera Universitaria Careggi (AOUC), I-50134 Florence, Italy, Division of General and Oncologic Surgery, Department of Oncology, Azienda Ospedaliera Universitaria Careggi (AOUC), I-50134 Florence, Italy, General Anatomopathology and Molecular Oncogenetics – AOU City of Health and Science of Turin, I-10126 Turin, Italy
Published online on: May 16, 2016 https://doi.org/10.3892/ijo.2016.3524
Pages: 393-401

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with an average survival of 4-6 months following diagnosis. Surgical resection is the only treatment with curative intent, but resectable PDAC patients are in the minority. Also, unlike other neoplasms, PDAC is resistant to conventional and targeted chemotherapy. Innovative treatments, such as immunotherapy, can be very important and the study of the immune response is fundamental. We previously demonstrated that PDAC patients show tumor-infiltrating T cells specific to α-enolase (ENO1), a glycolytic enzyme over-expressed by pancreatic tumor cells, which plays an important role in promoting cell migration and cancer metastasis. In the present study, we evaluate the functional anticancer proprieties of ENO1-specific T cells isolated from the peripheral blood of PDAC patients. Furthermore, comparing the T cell receptor repertoire of ENO1-specific peripheral and infiltrating tumor T cells from the same patient suggests that ENO1-specific T cells, despite having a different functional profile, can recirculate from the tumor to the periphery. Finally, of clinical relevance, the presence of peripheral ENO1-specific T cells has a prognostic value and significantly correlates with a longer survival.

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1	Hartwig W, Werner J, Jäger D, Debus J and Büchler MW: Improvement of surgical results for pancreatic cancer. Lancet Oncol. 14:e476–e485. 2013. View Article : Google Scholar : PubMed/NCBI
2	Wolfgang CL, Herman JM, Laheru DA, Klein AP, Erdek MA, Fishman EK and Hruban RH: Recent progress in pancreatic cancer. CA Cancer J Clin. 63:318–348. 2013. View Article : Google Scholar : PubMed/NCBI
3	Singh P, Srinivasan R and Wig JD: Major molecular markers in pancreatic ductal adenocarcinoma and their roles in screening, diagnosis, prognosis, and treatment. Pancreas. 40:644–652. 2011. View Article : Google Scholar : PubMed/NCBI
4	Loos M, Giese NA, Kleeff J, Giese T, Gaida MM, Bergmann F, Laschinger M, W Büchler M and Friess H: Clinical significance and regulation of the costimulatory molecule B7-H1 in pancreatic cancer. Cancer Lett. 268:98–109. 2008. View Article : Google Scholar : PubMed/NCBI
5	Bazhin AV, Shevchenko I, Umansky V, Werner J and Karakhanova S: Two immune faces of pancreatic adenocarcinoma: Possible implication for immunotherapy. Cancer Immunol Immunother. 63:59–65. 2014. View Article : Google Scholar
6	Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, Tosolini M, Camus M, Berger A, Wind P, et al: Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 313:1960–1964. 2006. View Article : Google Scholar : PubMed/NCBI
7	Ryschich E, Nötzel T, Hinz U, Autschbach F, Ferguson J, Simon I, Weitz J, Fröhlich B, Klar E, Büchler MW, et al: Control of T-cell-mediated immune response by HLA class I in human pancreatic carcinoma. Clin Cancer Res. 11:498–504. 2005.PubMed/NCBI
8	Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, Nakamura S, Enomoto K, Yagita H, Azuma M, et al: Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res. 13:2151–2157. 2007. View Article : Google Scholar : PubMed/NCBI
9	Park IH, Kong SY, Ro JY, Kwon Y, Kang JH, Mo HJ, Jung SY, Lee S, Lee KS, Kang HS, et al: Prognostic implications of tumor-infiltrating lymphocytes in association with programmed death ligand 1 expression in early-stage breast cancer. Clin Breast Cancer. 16:51–58. 2015. View Article : Google Scholar : PubMed/NCBI
10	Blank C, Gajewski TF and Mackensen A: Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: Implications for tumor immunotherapy. Cancer Immunol Immunother. 54:307–314. 2005. View Article : Google Scholar
11	Chen Y, Sun J, Zhao H, Zhu D, Zhi Q, Song S, Zhang L, He S, Kuang Y, Zhang Z, et al: The coexpression and clinical significance of costimulatory molecules B7-H1, B7-H3, and B7-H4 in human pancreatic cancer. Onco Targets Ther. 7:1465–1472. 2014. View Article : Google Scholar : PubMed/NCBI
12	Wadle A, Kubuschok B, Imig J, Wuellner B, Wittig C, Zwick C, Mischo A, Waetzig K, Romeike BF, Lindemann W, et al: Serological immune response to cancer testis antigens in patients with pancreatic cancer. Int J Cancer. 119:117–125. 2006. View Article : Google Scholar : PubMed/NCBI
13	Schmitz-Winnenthal FH, Galindo-Escobedo LV, Rimoldi D, Geng W, Romero P, Koch M, Weitz J, Krempien R, Niethammer AG, Beckhove P, et al: Potential target antigens for immunotherapy in human pancreatic cancer. Cancer Lett. 252:290–298. 2007. View Article : Google Scholar : PubMed/NCBI
14	Gnjatic S, Ritter E, Büchler MW, Giese NA, Brors B, Frei C, Murray A, Halama N, Zörnig I, Chen YT, et al: Seromic profiling of ovarian and pancreatic cancer. Proc Natl Acad Sci USA. 107:5088–5093. 2010. View Article : Google Scholar : PubMed/NCBI
15	Tomaino B, Cappello P, Capello M, Fredolini C, Ponzetto A, Novarino A, Ciuffreda L, Bertetto O, De Angelis C, Gaia E, et al: Autoantibody signature in human ductal pancreatic adenocarcinoma. J Proteome Res. 6:4025–4031. 2007. View Article : Google Scholar : PubMed/NCBI
16	Kubuschok B, Neumann F, Breit R, Sester M, Schormann C, Wagner C, Sester U, Hartmann F, Wagner M, Remberger K, et al: Naturally occurring T-cell response against mutated p21 ras oncoprotein in pancreatic cancer. Clin Cancer Res. 12:1365–1372. 2006. View Article : Google Scholar : PubMed/NCBI
17	Wenandy L, Sørensen RB, Sengeløv L, Svane IM, thor Straten P and Andersen MH: The immunogenicity of the hTERT540-548 peptide in cancer. Clin Cancer Res. 14:4–7. 2008. View Article : Google Scholar : PubMed/NCBI
18	Gjertsen MK, Bakka A, Breivik J, Saeterdal I, Solheim BG, Søreide O, Thorsby E and Gaudernack G: Vaccination with mutant ras peptides and induction of T-cell responsiveness in pancreatic carcinoma patients carrying the corresponding RAS mutation. Lancet. 346:1399–1400. 1995. View Article : Google Scholar : PubMed/NCBI
19	Wobser M, Keikavoussi P, Kunzmann V, Weininger M, Andersen MH and Becker JC: 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. 55:1294–1298. 2006. View Article : Google Scholar
20	Yamaguchi K, Enjoji M and Tsuneyoshi M: Pancreatoduodenal carcinoma: A clinicopathologic study of 304 patients and immunohistochemical observation for CEA and CA19-9. J Surg Oncol. 47:148–154. 1991. View Article : Google Scholar : PubMed/NCBI
21	Komoto M, Nakata B, Amano R, Yamada N, Yashiro M, Ohira M, Wakasa K and Hirakawa K: HER2 overexpression correlates with survival after curative resection of pancreatic cancer. Cancer Sci. 100:1243–1247. 2009. View Article : Google Scholar : PubMed/NCBI
22	Heller A, Zörnig I, Müller T, Giorgadze K, Frei C, Giese T, Bergmann F, Schmidt J, Werner J, Buchler MW, et al: Immunogenicity of SEREX-identified antigens and disease outcome in pancreatic cancer. Cancer Immunol Immunother. 59:1389–1400. 2010. View Article : Google Scholar : PubMed/NCBI
23	Cappello P, Tomaino B, Chiarle R, Ceruti P, Novarino A, Castagnoli C, Migliorini P, Perconti G, Giallongo A, Milella M, et al: An integrated humoral and cellular response is elicited in pancreatic cancer by alpha-enolase, a novel pancreatic ductal adenocarcinoma-associated antigen. Int J Cancer. 125:639–648. 2009. View Article : Google Scholar : PubMed/NCBI
24	Amedei A, Niccolai E, Benagiano M, Della Bella C, Cianchi F, Bechi P, Taddei A, Bencini L, Farsi M, Cappello P, et al: 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. Cancer Immunol Immunother. 62:1249–1260. 2013. View Article : Google Scholar : PubMed/NCBI
25	Capello M, Ferri-Borgogno S, Cappello P and Novelli F: α-Enolase: A promising therapeutic and diagnostic tumor target. FEBS J. 278:1064–1074. 2011. View Article : Google Scholar : PubMed/NCBI
26	Tomaino B, Cappello P, Capello M, Fredolini C, Sperduti I, Migliorini P, Salacone P, Novarino A, Giacobino A, Ciuffreda L, et al: Circulating autoantibodies to phosphorylated α-enolase are a hallmark of pancreatic cancer. J Proteome Res. 10:105–112. 2011. View Article : Google Scholar
27	Cappello P, Rolla S, Chiarle R, Principe M, Cavallo F, Perconti G, Feo S, Giovarelli M and Novelli F: Vaccination with ENO1 DNA prolongs survival of genetically engineered mice with pancreatic cancer. Gastroenterology. 144:1098–1106. 2013. View Article : Google Scholar : PubMed/NCBI
28	De Monte L, Reni M, Tassi E, Clavenna D, Papa I, Recalde H, Braga M, Di Carlo V, Doglioni C and Protti MP: 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. 208:469–478. 2011. View Article : Google Scholar : PubMed/NCBI
29	Linehan DC and Goedegebuure PS: CD25⁺ CD4⁺ regulatory T-cells in cancer. Immunol Res. 32:155–168. 2005. View Article : Google Scholar
30	Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doher ty G, Drebin JA, Strasberg SM, Eberlein TJ, Goedegebuure PS, et al: Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol. 169:2756–2761. 2002. View Article : Google Scholar : PubMed/NCBI
31	Bettelli E, Oukka M and Kuchroo VK: T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol. 8:345–350. 2007. View Article : Google Scholar : PubMed/NCBI
32	Kryczek I, Wei S, Zou L, Altuwaijri S, Szeliga W, Kolls J, Chang A and Zou W: Cutting edge: Th17 and regulatory T cell dynamics and the regulation by IL-2 in the tumor microenvironment. J Immunol. 178:6730–6733. 2007. View Article : Google Scholar : PubMed/NCBI
33	Zhang B, Rong G, Wei H, Zhang M, Bi J, Ma L, Xue X, Wei G, Liu X and Fang G: The prevalence of Th17 cells in patients with gastric cancer. Biochem Biophys Res Commun. 374:533–537. 2008. View Article : Google Scholar : PubMed/NCBI
34	Koyama K, Kagamu H, Miura S, Hiura T, Miyabayashi T, Itoh R, Kuriyama H, Tanaka H, Tanaka J, Yoshizawa H, et al: 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. 14:6770–6779. 2008. View Article : Google Scholar : PubMed/NCBI
35	Warshaw AL and Fernández-del Castillo C: Pancreatic carcinoma. N Engl J Med. 326:455–465. 1992. View Article : Google Scholar : PubMed/NCBI
36	Amedei A, Della Bella C, Niccolai E, Stanflin N, Benagiano M, Duranti R, Del Prete G, Murphy TF and D'Elios MM: Moraxella catarrhalis-specific Th1 cells in BAL fluids of chronic obstructive pulmonary disease patients. Int J Immunopathol Pharmacol. 22:979–990. 2009.
37	Amedei A, Niccolai E, Della Bella C, Cianchi F, Trallori G, Benagiano M, Bencini L, Bernini M, Farsi M, Moretti R, et al: Characterization of tumor antigen peptide-specific T cells isolated from the neoplastic tissue of patients with gastric adenocarcinoma. Cancer Immunol Immunother. 58:1819–1830. 2009. View Article : Google Scholar : PubMed/NCBI
38	van Dongen JJ, Langerak AW, Brüggemann M, Evans PA, Hummel M, Lavender FL, Delabesse E, Davi F, Schuuring E, García-Sanz R, et al: Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: Report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia. 17:2257–2317. 2003. View Article : Google Scholar : PubMed/NCBI
39	Nagorsen D, Scheibenbogen C, Schaller G, Leigh B, Schmittel A, Letsch A, Thiel E and Keilholz U: Differences in T-cell immunity toward tumor-associated antigens in colorectal cancer and breast cancer patients. Int J Cancer. 105:221–225. 2003. View Article : Google Scholar : PubMed/NCBI
40	Lippitz BE: Cytokine patterns in patients with cancer: A systematic review. Lancet Oncol. 14:e218–e228. 2013. View Article : Google Scholar : PubMed/NCBI
41	Berlin C, Berg EL, Briskin MJ, Andrew DP, Kilshaw PJ, Holzmann B, Weissman IL, Hamann A and Butcher EC: Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell. 74:185–195. 1993. View Article : Google Scholar : PubMed/NCBI
42	Rott LS, Briskin MJ, Andrew DP, Berg EL and Butcher EC: A fundamental subdivision of circulating lymphocytes defined by adhesion to mucosal addressin cell adhesion molecule-1. Comparison with vascular cell adhesion molecule-1 and correlation with beta 7 integrins and memory differentiation. J Immunol. 156:3727–3736. 1996.PubMed/NCBI
43	Brandacher G, Winkler C, Schroecksnadel K, Margreiter R and Fuchs D: Antitumoral activity of interferon-gamma involved in impaired immune function in cancer patients. Curr Drug Metab. 7:599–612. 2006. View Article : Google Scholar : PubMed/NCBI
44	Zaidi MR and Merlino G: The two faces of interferon-γ in cancer. Clin Cancer Res. 17:6118–6124. 2011. View Article : Google Scholar : PubMed/NCBI
45	Neurath MF and Finotto S: The emerging role of T cell cytokines in non-small cell lung cancer. Cytokine Growth Factor Rev. 23:315–322. 2012. View Article : Google Scholar : PubMed/NCBI
46	Hemdan NY: Anti-cancer versus cancer-promoting effects of the interleukin-17-producing T helper cells. Immunol Lett. 149:123–133. 2013. View Article : Google Scholar
47	Bidard FC, Huguet F, Louvet C, Mineur L, Bouché O, Chibaudel B, Artru P, Desseigne F, Bachet JB, Mathiot C, et al: Circulating tumor cells in locally advanced pancreatic adenocarcinoma: The ancillary CirCe 07 study to the LAP 07 trial. Ann Oncol. 24:2057–2061. 2013. View Article : Google Scholar : PubMed/NCBI
48	Tjensvoll K, Nordgård O and Smaaland R: Circulating tumor cells in pancreatic cancer patients: Methods of detection and clinical implications. Int J Cancer. 134:1–8. 2014. View Article : Google Scholar
49	Niccolai E, Prisco D, D'Elios MM and Amedei A: What is recent in pancreatic cancer immunotherapy? BioMed Res Int. 2013:4923722013. View Article : Google Scholar : PubMed/NCBI