Identification of a tumor-reactive T-cell repertoire in the immune infiltrate of patients with resectable pancreatic ductal adenocarcinoma

OncoImmunology

Volumn 5, Issue 12, 2016, Pages

  Poschke, Isabel ^a   Faryna, Marta ^b   Bergmann, Frank ^c   Flossdorf, Michael ^d   Lauenstein, Claudia ^a   Hermes, Jennifer ^a   Hinz, Ulf ^c   Hank, Thomas ^c   Ehrenberg, Roland ^a,c   Volkmar, Michael ^a   Loewer, Martin ^e   Glimm, Hanno ^a   Hackert, Thilo ^c   Sprick, Martin R ^a,f   Höfer, Thomas ^d   Trumpp, Andreas ^a,f   Halama, Niels ^c   Hassel, Jessica C ^c   Strobel, Oliver ^c   Büchler, Markus ^c   Sahin, Ugur ^b,e   Offringa, Rienk ^a,c   more..

^a GERMAN CANCER RESEARCH CENTER DKFZ   (Germany)

^b BIONTECH AG   (Germany)

^c UNIVERSITY HOSPITAL HEIDELBERG   (Germany)

^d UNIVERSITY OF HEIDELBERG   (Germany)

^e UNIVERSITY MEDICAL CENTER MAINZ   (Germany)

^f HI STEM GGmbH   (Germany)

Author keywords

Adoptive T cell therapy; pancreatic ductal adenocarcinoma; T cell receptor (TCR) repertoire; tertiary lymphoid structures; tumor infiltrating lymphocytes

Indexed keywords

T LYMPHOCYTE RECEPTOR;

ARTICLE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL INFILTRATION; CONTROLLED STUDY; FEMALE; FLOW CYTOMETRY; GENOTYPE PHENOTYPE CORRELATION; HUMAN; HUMAN CELL; HUMAN TISSUE; IMAGE ANALYSIS; IMMUNOHISTOCHEMISTRY; IN VITRO STUDY; MAJOR CLINICAL STUDY; MALE; MELANOMA; PANCREAS ADENOCARCINOMA; PERIPHERAL BLOOD MONONUCLEAR CELL; REGRESSION ANALYSIS; RNA EXTRACTION; SEQUENCE ANALYSIS; SURVIVAL ANALYSIS; T LYMPHOCYTE; TUMOR BIOPSY;

EID: 84999711707     PISSN: 21624011     EISSN: 2162402X     Source Type: Journal    
DOI: 10.1080/2162402X.2016.1240859     Document Type: Article

References (54)

1. Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy:toward combination strategies with curative potential. Cell 2015; 161:205-14; PMID:25860605; http://dx.doi.org/10.1016/j.cell.2015.03.030
2. Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade:a common denominator approach to cancer therapy. Cancer Cell 2015; 27:450-61; PMID:25858804; http://dx.doi.org/10.1016/j.ccell.2015.03.001
3. Gillen S, Schuster T, Meyer Zum Buschenfelde C, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer:a systematic review and meta-analysis of response and resection percentages. PLoS Med 2010; 7:e1000267; PMID:20422030; http://dx.doi.org/10.1371/journal.pmed.1000267
4. Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011; 364:1817-25; PMID:21561347; http://dx.doi.org/10.1056/NEJMoa1011923
5. Hartwig W, Werner J, Jager D, Debus J, Buchler MW. Improvement of surgical results for pancreatic cancer. Lancet Oncol 2013; 14:e476-85; PMID:24079875; http://dx.doi.org/10.1016/S1470-2045(13)70172-4
6. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012; 366:2455-65; PMID:22658128; http://dx.doi.org/10.1056/NEJMoa1200694
7. Royal RE, Levy C, Turner K, Mathur A, Hughes M, Kammula US, Sherry RM, Topalian SL, Yang JC, Lowy I, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother 2010; 33:828-33; PMID:20842054; http://dx.doi.org/10.1097/CJI.0b013e3181eec14c
8. Beatty GL, Chiorean EG, Fishman MP, Saboury B, Teitelbaum UR, Sun W, Huhn RD, Song W, Li D, Sharp LL, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 2011; 331:1612-6; PMID:21436454; http://dx.doi.org/10.1126/science.1198443
9. Le DT, Wang-Gillam A, Picozzi V, Greten TF, Crocenzi T, Springett G, Morse M, Zeh H, Cohen D, Fine RL, et al. Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol 2015; 33:1325-33; PMID:25584002; http://dx.doi.org/10.1200/JCO.2014.57.4244
10. Lutz ER, Wu AA, Bigelow E, Sharma R, Mo G, Soares K, Solt S, Dorman A, Wamwea A, Yager A, et al. Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. Cancer Immunol Res 2014; 2:616-31; PMID:24942756; http://dx.doi.org/10.1158/2326-6066.CIR-14-0027
11. Soares KC, Rucki AA, Wu AA, Olino K, Xiao Q, Chai Y, Wamwea A, Bigelow E, Lutz E, Liu L, et al. PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors. J Immunother 2015; 38:1-11; PMID:25415283; http://dx.doi.org/10.1097/CJI.0000000000000062
12. Hartwig W, Hackert T, Hinz U, Gluth A, Bergmann F, Strobel O, Büchler MW, Werner J. Pancreatic cancer surgery in the new millennium:better prediction of outcome. Ann Surg 2011; 254:311-9; PMID:21606835; http://dx.doi.org/10.1097/SLA.0b013e31821fd334
13. Halama N, Michel S, Kloor M, Zoernig I, Benner A, Spille A, Pommerencke T, von Knebel DM, Folprecht G, Luber B, et al. Localization and density of immune cells in the invasive margin of human colorectal cancer liver metastases are prognostic for response to chemotherapy. Cancer Res 2011; 71:5670-7; PMID:21846824; http://dx.doi.org/10.1158/0008-5472.CAN-11-0268
14. Poschke I, Lovgren T, Adamson L, Nystrom M, Andersson E, Hansson J, Tell R, Masucci GV, Kiessling R. A phase I clinical trial combining dendritic cell vaccination with adoptive T-cell transfer in patients with stage IV melanoma. Cancer Immunol Immunother 2014; 63:1061-71; PMID:24993563; http://dx.doi.org/10.1007/s00262-014-1575-2
15. van der Burg SH, Piersma SJ, de Jong A, van der Hulst JM, Kwappenberg KM, van den Hende M, Welters MJ, Van Rood JJ, Fleuren GJ, et al. Association of cervical cancer with the presence of CD4+ regulatory T-cells specific for human papillomavirus antigens. Proc Natl Acad Sci U S A 2007; 104:12087-92; PMID:17615234; http://dx.doi.org/10.1073/pnas.0704672104
16. Tran KQ, Zhou J, Durflinger KH, Langhan MM, Shelton TE, Wunderlich JR, Robbins PF, Rosenberg SA, Dudley ME. Minimally cultured tumor-infiltrating lymphocytes display optimal characteristics for adoptive cell therapy. J Immunother 2008; 31:742-51; PMID:18779745; http://dx.doi.org/10.1097/CJI.0b013e31818403d5
17. Halama N, Zoernig I, Spille A, Westphal K, Schirmacher P, Jaeger D, Grabe N. Estimation of immune cell densities in immune cell conglomerates:an approach for high-throughput quantification. PLoS One 2009; 4:e7847; PMID:19924291; http://dx.doi.org/10.1371/journal.pone.0007847
18. Neesse A, Algul H, Tuveson DA, Gress TM. Stromal biology and therapy in pancreatic cancer:a changing paradigm. Gut 2015; 64:1476-84; PMID:25994217; http://dx.doi.org/10.1136/gutjnl-2015-309304
19. Whatcott CJ, Han H, Von Hoff DD. Orchestrating the tumor microenvironment to improve survival for patients with pancreatic cancer:normalization, not destruction. Cancer J 2015; 21:299-306; PMID:26222082; http://dx.doi.org/10.1097/PPO.0000000000000140
20. Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 2015; 348:62-8; PMID:25838374; http://dx.doi.org/10.1126/science.aaa4967
21. Geukes Foppen MH, Donia M, Svane IM, Haanen JB. Tumor-infiltrating lymphocytes for the treatment of metastatic cancer. Mol Oncol 2015; 9(10):1918-35; PMID:26578452; http://dx.doi.org/10.1016/j.molonc.2015.10.018
22. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014; 515:568-71; PMID:25428505; http://dx.doi.org/10.1038/nature13954
23. Cha E, Klinger M, Hou Y, Cummings C, Ribas A, Faham M, Fong L. Improved survival with T-cell clonotype stability after anti-CTLA-4 treatment in cancer patients. Sci Transl Med 2014; 6:238ra70; PMID:24871131; http://dx.doi.org/10.1126/scitranslmed.3008211
24. Nourshargh S, Alon R. Leukocyte migration into inflamed tissues. Immunity 2014; 41:694-707; PMID:25517612; http://dx.doi.org/10.1016/j.immuni.2014.10.008
25. Chacon JA, Wu RC, Sukhumalchandra P, Molldrem JJ, Sarnaik A, Pilon-Thomas S, Weber J, Hwu P, Radvanyi L. Co-stimulation through 4-1BB/CD137 improves the expansion and function of CD8(+) melanoma tumor-infiltrating lymphocytes for adoptive T-cell therapy. PLoS One 2013; 8:e60031; PMID:23560068; http://dx.doi.org/10.1371/journal.pone.0060031
26. Ye Q, Song DG, Poussin M, Yamamoto T, Best A, Li C, Coukos G, Powell DJ. CD137 accurately identifies and enriches for naturally occurring tumor-reactive T-cells in tumor. Clin Cancer Res 2014; 20:44-55; PMID:24045181; http://dx.doi.org/10.1158/1078-0432.CCR-13-0945
27. Gros A, Robbins PF, Yao X, Li YF, Turcotte S, Tran E, Wunderlich JR, Mixon A, Farid S, Dudley ME, et al. PD-1 identifies the patient-specific CD8(+) tumor-reactive repertoire infiltrating human tumors. J Clin Invest 2014; 124:2246-59; PMID:24667641; http://dx.doi.org/10.1172/JCI73639
28. Chen Z, Zhang C, Pan Y, Xu R, Xu C, Chen Z, Lu Z, Ke Y. T-cell receptor β-chain repertoire analysis reveals intratumour heterogeneity of tumour-infiltrating lymphocytes in oesophageal squamous cell carcinoma. J Pathol 2016; 239(4):450-8; PMID:27171315; http://dx.doi.org/10.1002/path.4742
29. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science 2015; 348:69-74; PMID:25838375; http://dx.doi.org/10.1126/science.aaa4971
30. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Børresen-Dale A-L, et al. Signatures of mutational processes in human cancer. Nature 2013; 500:415-21; PMID:23945592; http://dx.doi.org/10.1038/nature12477
31. Tran E, Ahmadzadeh M, Lu YC, Gros A, Turcotte S, Robbins PF, Gartner JJ, Zheng Z, Li YF, Ray S, et al. Immunogenicity of somatic mutations in human gastrointestinal cancers. Science 2015; 350:1387-1390; PMID:26516200; http://dx.doi.org/10.1126/science.aad1253
32. Kreiter S, Vormehr M, van de Roemer N, Diken M, Lower M, Diekmann J, Boegel S, Schrörs B, Vascotto F, Castle JC, et al. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 2015; 520:692-6; PMID:25901682; http://dx.doi.org/10.1038/nature14426
33. Linnemann C, van Buuren MM, Bies L, Verdegaal EM, Schotte R, Calis JJ, Behjati S, Velds A, Hilkmann H, Atmioui DE, et al. High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T-cells in human melanoma. Nat Med 2015; 21:81-5; PMID:25531942; http://dx.doi.org/10.1038/nm.3773
34. Tran E, Turcotte S, Gros A, Robbins PF, Lu YC, Dudley ME, Wunderlich JR, Somerville RP, Hogan K, Hinrichs CS, et al. Cancer immunotherapy based on mutation-specific CD4+ T-cells in a patient with epithelial cancer. Science 2014; 344:641-5; PMID:24812403; http://dx.doi.org/10.1126/science.1251102
35. Klein L, Kyewski B, Allen PM, Hogquist KA. Positive and negative selection of the T-cell repertoire:what thymocytes see (and don't see). Nat Rev Immunol 2014; 14:377-91; PMID:24830344; http://dx.doi.org/10.1038/nri3667
36. 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 2013; 62:1249-60; PMID:23640603; http://dx.doi.org/10.1007/s00262-013-1429-3
37. Suso EM, Dueland S, Rasmussen AM, Vetrhus T, Aamdal S, Kvalheim G, Gaudernack G. hTERT mRNA dendritic cell vaccination:complete response in a pancreatic cancer patient associated with response against several hTERT epitopes. Cancer Immunol Immunother 2011; 60:809-18; PMID:21365467; http://dx.doi.org/10.1007/s00262-011-0991-9
38. Lauwen MM, Zwaveling S, de Quartel L, Ferreira Mota SC, Grashorn JA, Melief CJ, van der Burg SH, Offringa R. Self-tolerance does not restrict the CD4+ T-helper response against the p53 tumor antigen. Cancer Res 2008; 68:893-900; PMID:18245492; http://dx.doi.org/10.1158/0008-5472.CAN-07-3166
39. Ino Y, Yamazaki-Itoh R, Shimada K, Iwasaki M, Kosuge T, Kanai Y, Hiraoka N. Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer. Br J Cancer 2013; 108:914-23; PMID:23385730; http://dx.doi.org/10.1038/bjc.2013.32
40. Ene-Obong A, Clear AJ, Watt J, Wang J, Fatah R, Riches JC, Marshall JF, Chin-Aleong J, Chelala C, Gribben JG, et al. Activated pancreatic stellate cells sequester CD8+ T-cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma. Gastroenterology 2013; 145:1121-32; PMID:23891972; http://dx.doi.org/10.1053/j.gastro.2013.07.025
41. Fukunaga A, Miyamoto M, Cho Y, Murakami S, Kawarada Y, Oshikiri T, Kato K, Kurokawa T, Suzuoki M, Nakakubo Y, et al. CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma. Pancreas 2004; 28:e26-31; PMID:14707745; http://dx.doi.org/10.1097/00006676-200401000-00023
42. Hiraoka N, Onozato K, Kosuge T, Hirohashi S. Prevalence of FOXP3+ regulatory T-cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res 2006; 12:5423-34; PMID:17000676; http://dx.doi.org/10.1158/1078-0432.CCR-06-0369
43. De Monte L, Reni M, Tassi E, Clavenna D, Papa I, Recalde H, Braga M, Di Carlo V, Doglioni C, 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 2011; 208:469-78; PMID:21339327; http://dx.doi.org/10.1084/jem.20101876
44. Hiraoka N, Ino Y, Yamazaki-Itoh R, Kanai Y, Kosuge T, Shimada K. Intratumoral tertiary lymphoid organ is a favourable prognosticator in patients with pancreatic cancer. Br J Cancer 2015; 112:1782-90; PMID:25942397; http://dx.doi.org/10.1038/bjc.2015.145
45. Castino GF, Cortese N, Capretti G, Serio S, Di Caro G, Mineri R, Magrini E, Grizzi F, Cappello P, Novelli F, et al. Spatial distribution of B cells predicts prognosis in human pancreatic adenocarcinoma. Oncoimmunology 2016; 5:e1085147; PMID:27141376; http://dx.doi.org/10.1080/2162402X.2015.1085147
46. Coppola D, Nebozhyn M, Khalil F, Dai H, Yeatman T, Loboda A, Mulé JJ. Unique ectopic lymph node-like structures present in human primary colorectal carcinoma are identified by immune gene array profiling. Am J Pathol 2011; 179:37-45; PMID:21703392; http://dx.doi.org/10.1016/j.ajpath.2011.03.007
47. Dieu-Nosjean MC, Antoine M, Danel C, Heudes D, Wislez M, Poulot V, Rabbe N, Laurans L, Tartour E, de Chaisemartin L, et al. Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol 2008; 26:4410-7; PMID:18802153; http://dx.doi.org/10.1200/JCO.2007.15.0284
48. Martinet L, Garrido I, Filleron T, Le Guellec S, Bellard E, Fournie JJ, Rochaix P, Girard JP. Human solid tumors contain high endothelial venules:association with T- and B-lymphocyte infiltration and favorable prognosis in breast cancer. Cancer Res 2011; 71:5678-87; PMID:21846823; http://dx.doi.org/10.1158/0008-5472.CAN-11-0431
49. Snyder A, Wolchok JD, Chan TA. Genetic basis for clinical response to CTLA-4 blockade. N Engl J Med 2015; 372:783; PMID:25693024; http://dx.doi.org/10.1056/NEJMc1415938
50. Van Allen EM, Miao D, Schilling B, Shukla SA, Blank C, Zimmer L, Sucker A, Hillen U, Geukes Foppen MH, Goldinger SM, et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 2015; 350:207-11; PMID:26359337; http://dx.doi.org/10.1126/science.aad0095
51. Feig C, Jones JO, Kraman M, Wells RJ, Deonarine A, Chan DS, Connell CM, Roberts EW, Zhao Q, Caballero OL, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A 2013; 110:20212-7; PMID:24277834; http://dx.doi.org/10.1073/pnas.1320318110
52. Hartmann N, Giese NA, Giese T, Poschke I, Offringa R, Werner J, Ryschich E. Prevailing role of contact guidance in intrastromal T-cell trapping in human pancreatic cancer. Clin Cancer Res 2014; 20:3422-33; PMID:24763614; http://dx.doi.org/10.1158/1078-0432.CCR-13-2972
53. Offringa R, Glennie MJ. Development of next-generation immunomodulatory antibodies for cancer therapy through optimization of the IgG framework. Cancer Cell 2015; 28:273-5; PMID:26373272; http://dx.doi.org/10.1016/j.ccell.2015.08.008
54. Boisguerin V, Castle JC, Loewer M, Diekmann J, Mueller F, Britten CM, Kreiter S, Türeci Ö, Sahin U. Translation of genomics-guided RNA-based personalised cancer vaccines:towards the bedside. Br J Cancer 2014; 111:1469-75; PMID:25314223; http://dx.doi.org/10.1038/bjc.2013.820