Evolution of the Immune Landscape During Progression of Pancreatic Intraductal Papillary Mucinous Neoplasms to Invasive Cancer

Overview

Journal EBioMedicine

Specialty Biomedical Engineering

Date 2020 Apr 8

PMID 32259711

Citations 27

Authors

Susanne Roth

Katharina Zamzow

Matthias M Gaida

Mathias Heikenwalder

Christine Tjaden

Ulf Hinz

Promita Bose

Christoph W Michalski

Thilo Hackert

Affiliations

Soon will be listed here.

Abstract

Background: Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions of pancreatic cancer, which is characterized by an immunosuppressive microenvironment. Yet, the spatial distribution of the immune infiltrate and how it changes during IPMN progression is just beginning to be understood.

Methods: We obtained tissue samples from patients who underwent pancreatic surgery for IPMN, and performed comprehensive immunohistochemical analyses to investigate the clinical significance, composition and spatial organization of the immune microenvironment during progression of IPMNs. Survival analysis of pancreatic cancer patients was stratified by tumour infiltrating immune cell subtypes.

Findings: The immune microenvironment evolves from a diverse T cell mixture, comprising CD8 T cells, Th/c1 and Th/c2 as major players combined with Th9, Th/c17, Th22, and Treg cells in low-grade IPMN, to a Treg dominated immunosuppressive state in invasive pancreatic cancer. Organized lymphoid clusters formed in IPMN surrounding stroma and accumulated immunosuppressive cell types during tumour progression. Survival of pancreatic cancer patients correlated with Th2 signatures in the tumour microenvironment.

Interpretation: The major change with regards to T cell composition during IPMN progression occurs at the step of tissue invasion, indicating that malignant transformation only occurs when tumour immune surveillance is overcome. This suggests that novel immunotherapies that would boost spontaneous antitumor immunity at premalignant states could prevent pancreatic cancer development.

Funding: The present work was supported by German Cancer Aid grants (70,112,720 and 70,113,167) to S. R., and the Olympia Morata Programme of the Medical Faculty of Heidelberg University to S. R.

Citing Articles

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References

McAllister F, Bailey J, Alsina J, Nirschl C, Sharma R, Fan H . Oncogenic Kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia. Cancer Cell. 2014; 25(5):621-37. PMC: 4072043. DOI: 10.1016/j.ccr.2014.03.014. View

Hruban R, Takaori K, Klimstra D, Adsay N, Albores-Saavedra J, Biankin A . An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol. 2004; 28(8):977-87. DOI: 10.1097/01.pas.0000126675.59108.80. View

Stromnes I, Hulbert A, Pierce R, Greenberg P, Hingorani S . T-cell Localization, Activation, and Clonal Expansion in Human Pancreatic Ductal Adenocarcinoma. Cancer Immunol Res. 2017; 5(11):978-991. PMC: 5802342. DOI: 10.1158/2326-6066.CIR-16-0322. View

Fang D, Zhu J . Dynamic balance between master transcription factors determines the fates and functions of CD4 T cell and innate lymphoid cell subsets. J Exp Med. 2017; 214(7):1861-1876. PMC: 5502437. DOI: 10.1084/jem.20170494. View

Chaput N, Conforti R, Viaud S, Spatz A, Zitvogel L . The Janus face of dendritic cells in cancer. Oncogene. 2008; 27(45):5920-31. DOI: 10.1038/onc.2008.270. View

Kryczek I, Lin Y, Nagarsheth N, Peng D, Zhao L, Zhao E . IL-22(+)CD4(+) T cells promote colorectal cancer stemness via STAT3 transcription factor activation and induction of the methyltransferase DOT1L. Immunity. 2014; 40(5):772-784. PMC: 4032366. DOI: 10.1016/j.immuni.2014.03.010. View

Lutz E, Wu A, Bigelow E, Sharma R, Mo G, Soares K . Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. Cancer Immunol Res. 2014; 2(7):616-31. PMC: 4082460. DOI: 10.1158/2326-6066.CIR-14-0027. View

Wartenberg M, Cibin S, Zlobec I, Vassella E, Eppenberger-Castori S, Terracciano L . Integrated Genomic and Immunophenotypic Classification of Pancreatic Cancer Reveals Three Distinct Subtypes with Prognostic/Predictive Significance. Clin Cancer Res. 2018; 24(18):4444-4454. DOI: 10.1158/1078-0432.CCR-17-3401. View

Hackert T, Fritz S, Klauss M, Bergmann F, Hinz U, Strobel O . Main-duct Intraductal Papillary Mucinous Neoplasm: High Cancer Risk in Duct Diameter of 5 to 9 mm. Ann Surg. 2015; 262(5):875-80. DOI: 10.1097/SLA.0000000000001462. View

10.

Caro G, Cortese N, Castino G, Grizzi F, Gavazzi F, Ridolfi C . Dual prognostic significance of tumour-associated macrophages in human pancreatic adenocarcinoma treated or untreated with chemotherapy. Gut. 2015; 65(10):1710-20. DOI: 10.1136/gutjnl-2015-309193. View

11.

Alam M, Gaida M, Bergmann F, Lasitschka F, Giese T, Giese N . Selective inhibition of the p38 alternative activation pathway in infiltrating T cells inhibits pancreatic cancer progression. Nat Med. 2015; 21(11):1337-43. PMC: 4636461. DOI: 10.1038/nm.3957. View

12.

Dieu-Nosjean M, Giraldo N, Kaplon H, Germain C, Fridman W, Sautes-Fridman C . Tertiary lymphoid structures, drivers of the anti-tumor responses in human cancers. Immunol Rev. 2016; 271(1):260-75. DOI: 10.1111/imr.12405. View

13.

De Monte L, Reni M, Tassi E, Clavenna D, Papa I, Recalde H . 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(3):469-78. PMC: 3058573. DOI: 10.1084/jem.20101876. View

14.

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(11):1782-90. PMC: 4647237. DOI: 10.1038/bjc.2015.145. View

15.

Hu B, Qiu-Lan H, Lei R, Shi C, Jiang H, Qin S . Interleukin-9 Promotes Pancreatic Cancer Cells Proliferation and Migration via the miR-200a/Beta-Catenin Axis. Biomed Res Int. 2017; 2017:2831056. PMC: 5352879. DOI: 10.1155/2017/2831056. View

16.

Marchegiani G, Mino-Kenudson M, Sahora K, Morales-Oyarvide V, Thayer S, Ferrone C . IPMN involving the main pancreatic duct: biology, epidemiology, and long-term outcomes following resection. Ann Surg. 2014; 261(5):976-83. PMC: 5614498. DOI: 10.1097/SLA.0000000000000813. View

17.

Mousset C, Hobo W, Woestenenk R, Preijers F, Dolstra H, van der Waart A . Comprehensive Phenotyping of T Cells Using Flow Cytometry. Cytometry A. 2019; 95(6):647-654. DOI: 10.1002/cyto.a.23724. View

18.

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(18):5423-34. DOI: 10.1158/1078-0432.CCR-06-0369. View

19.

Crippa S, Bassi C, Salvia R, Malleo G, Marchegiani G, Rebours V . Low progression of intraductal papillary mucinous neoplasms with worrisome features and high-risk stigmata undergoing non-operative management: a mid-term follow-up analysis. Gut. 2016; 66(3):495-506. DOI: 10.1136/gutjnl-2015-310162. View

20.

Ene-Obong A, Clear A, Watt J, Wang J, Fatah R, Riches J . Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma. Gastroenterology. 2013; 145(5):1121-32. PMC: 3896919. DOI: 10.1053/j.gastro.2013.07.025. View