IL22BP Mediates the Antitumor Effects of Lymphotoxin Against Colorectal Tumors in Mice and Humans

被引：35

作者：

Kempski, Jan ^{[1
,2
]}

Giannou, Anastasios D. ^{[1
]}

Riecken, Kristoffer ^{[3
]}

Zhao, Lilan ^{[4
,19
]}

Steglich, Babett ^{[1
]}

Luecke, Joeran ^{[1
]}

Garcia-Perez, Laura ^{[1
]}

Karstens, Karl-Frederick ^{[4
]}

Woestemeier, Anna ^{[4
]}

Nawrocki, Mikolaj ^{[1
]}

Pelczar, Penelope ^{[1
]}

Witkowski, Mario ^{[5
]}

Nilsson, Sven ^{[6
]}

Konczalla, Leonie ^{[4
]}

Shiri, Ahmad Mustafa ^{[1
]}

Kempska, Joanna ^{[7
]}

Wahib, Ramez ^{[4
]}

Brockmann, Leonie ^{[1
]}

Huber, Philipp ^{[1
]}

Gnirck, Ann-Christin ^{[8
]}

Turner, Jan-Eric ^{[8
]}

Zazara, Dimitra E. ^{[9
]}

Arck, Petra C. ^{[9
]}

Stein, Alexander ^{[6
]}

Simon, Ronald ^{[10
]}

Daubmann, Anne ^{[11
]}

Meiners, Jan ^{[4
]}

Perez, Daniel ^{[4
]}

Strowig, Till ^{[12
]}

Koni, Pandelakis ^{[13
]}

Kruglov, Andrey A. ^{[14
,15
]}

Sauter, Guido ^{[10
]}

Izbicki, Jakob R. ^{[4
]}

Guse, Andreas H. ^{[2
]}

Roesch, Thomas ^{[16
]}

Lohse, Ansgar W. ^{[1
]}

Flavell, Richard A. ^{[17
,18
]}

Gagliani, Nicola ^{[1
,4
]}

Huber, Samuel ^{[1
]}

机构：

[1] Univ Med Ctr Hamburg Eppendorf, Dept Med 1, Sect Mol Immunol & Gastroenterol, Hamburg, Germany

[2] Univ Med Ctr Hamburg Eppendorf, Dept Biochem & Mol Cell Biol, Calcium Signaling Grp, Hamburg, Germany

[3] Univ Med Ctr Hamburg Eppendorf, Res Dept Cell & Gene Therapy, Dept Stem Cell Transplantat, Hamburg, Germany

[4] Univ Med Ctr Hamburg Eppendorf, Dept Gen Visceral & Thorac Surg, Hamburg, Germany

[5] Charite, Inst Mikrobiol & Infektionsimmunol, Berlin, Germany

[6] Univ Med Ctr Hamburg Eppendorf, Dept Med 2, Hamburg, Germany

[7] Univ Med Ctr Hamburg Eppendorf, Dept Gynecol, Hamburg, Germany

[8] Univ Med Ctr Hamburg Eppendorf, Dept Med 3, Hamburg, Germany

[9] Univ Med Ctr Hamburg Eppendorf, Dept Obstet & Prenatal Med, Lab Expt Feto Maternal Med, Hamburg, Germany

[10] Univ Med Ctr Hamburg Eppendorf, Inst Pathol, Hamburg, Germany

[11] Univ Med Ctr Hamburg Eppendorf, Dept Med Biometry & Epidemiol, Hamburg, Germany

[12] Helmholtz Ctr Infect Res, Braunschweig, Germany

[13] Augusta Univ, Georgia Canc Ctr, Augusta, GA USA

[14] Leibniz Inst, German Rheumatism Res Ctr, Berlin, Germany

[15] Lomonosov Moscow State Univ, Belozersky Inst Phys Chem Biol & Biol Fac, Moscow, Russia

[16] Univ Med Ctr Hamburg Eppendorf, Dept Interdisciplinary Endoscopy, Hamburg, Germany

[17] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT USA

[18] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06510 USA

[19] Fujian Med Univ, Fujian Prov Hosp, Dept Gen Thorac Surg, Fuzhou 350003, Peoples R China

来源：

GASTROENTEROLOGY | 2020年 / 159卷 / 04期

基金：

欧洲研究理事会;

关键词：

Immune Regulation; Inflammation; Cytokine Signaling; Tumor Suppressor; INNATE LYMPHOID-CELLS; ONTOLOGY LEGO VECTORS; T-CELLS; GENE-EXPRESSION; BETA-RECEPTOR; INTERLEUKIN; 22; IMMUNE CELLS; IL-22; CANCER; INFLAMMATION;

D O I：

10.1053/j.gastro.2020.06.033

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

BACKGROUND & AIMS: Unregulated activity of interleukin (IL) 22 promotes intestinal tumorigenesis in mice. IL22 binds the antagonist IL22 subunit alpha 2 (IL22RA2, also called IL22BP). We studied whether alterations in IL22BP contribute to colorectal carcinogenesis in humans and mice. METHODS: We obtained tumor and nontumor tissues from patients with colorectal cancer (CRC) and measured levels of cytokines by quantitative polymerase chain reaction, flow cytometry, and immunohistochemistry. We measured levels of Il22bp messenger RNA in colon tissues from wild-type, Tnf(-/-), Lta(-/-), and Ltb(-/-) mice. Mice were given azoxymethane and dextran sodium sulfate to induce colitis and associated cancer or intracecal injections of MC38 tumor cells. Some mice were given inhibitors of lymphotoxin beta receptor (LTBR). Intestine tissues were analyzed by single-cell sequencing to identify cell sources of lymphotoxin. We performed immunohistochemistry analysis of colon tissue microarrays from patients with CRC (1475 tissue cores, contained tumor and nontumor tissues) and correlated levels of IL22BP with patient survival times. RESULTS: Levels of IL22BP were decreased in human colorectal tumors, compared with nontumor tissues, and correlated with levels of lymphotoxin. LTBR signaling was required for expression of IL22BP in colon tissues of mice. Wild-type mice given LTBR inhibitors had an increased tumor burden in both models, but LTBR inhibitors did not increase tumor growth in Il22bp(-/-) mice. Lymphotoxin directly induced expression of IL22BP in cultured human monocyte-derived dendritic cells via activation of nuclear factor kappa B. Reduced levels of IL22BP in colorectal tumor tissues were associated with shorter survival times of patients with CRC. CONCLUSIONS: Lymphotoxin signaling regulates expression of IL22BP in colon; levels of IL22BP are reduced in human colorectal tumors, associated with shorter survival times. LTBR signaling regulates expression of IL22BP in colon tumors in mice and cultured human dendritic cells. Patients with colorectal tumors that express low levels of IL22BP might benefit from treatment with an IL22 antagonist.

引用

页码：1417 / +

页数：17

共 59 条

[11] Interleukin-22: Immunobiology and Pathology [J].

Dudakov, Jarrod A. ;

Hanash, Alan M. ;

van den Brink, Marcel R. M. .

ANNUAL REVIEW OF IMMUNOLOGY VOL 33, 2015, 33 :747-785

[12] Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells [J].

Duhen, Thomas ;

Geiger, Rebekka ;

Jarrossay, David ;

Lanzavecchia, Antonio ;

Sallusto, Federica .

NATURE IMMUNOLOGY, 2009, 10 (08) :857-U72

[13] Thymic origin of intestinal αβ T cells revealed by fate mapping of RORγt+ cells [J].

Eberl, G ;

Littman, DR .

SCIENCE, 2004, 305 (5681) :248-251

[14] Molecular origins of cancer - Cancer immunology [J].

Finn, Olivera J. .

NEW ENGLAND JOURNAL OF MEDICINE, 2008, 358 (25) :2704-2715

[15] The immune contexture in human tumours: impact on clinical outcome [J].

Fridman, Wolf Herman ;

Pages, Franck ;

Sautes-Fridman, Catherine ;

Galon, Jerome .

NATURE REVIEWS CANCER, 2012, 12 (04) :298-306

[16] Type, density, and location of immune cells within human colorectal tumors predict clinical outcome [J].

Galon, Jerom ;

Costes, Anne ;

Sanchez-Cabo, Fatima ;

Kirilovsky, Amos ;

Mlecnik, Bernhard ;

Lagorce-Pages, Christine ;

Tosolini, Marie ;

Camus, Matthieu ;

Berger, Anne ;

Wind, Philippe ;

Zinzindohoue, Franck ;

Bruneval, Patrick ;

Cugnenc, Paul-Henri ;

Trajanoski, Zlatko ;

Fridman, Wolf-Herman ;

Pages, Franck .

SCIENCE, 2006, 313 (5795) :1960-1964

[17] Mast cells mediate malignant pleural effusion formation [J].

Giannou, Anastasios D. ;

Marazioti, Antonia ;

Spella, Magda ;

Kanellakis, Nikolaos I. ;

Apostolopoulou, Hara ;

Psallidas, Loannis ;

Prijovich, Zeljko M. ;

Vreka, Malamati ;

Zazara, Dimitra E. ;

Lilis, Loannis ;

Papaleonidopoulos, Vassilios ;

Kairi, Chrysoula A. ;

Patmanidi, Alexandra L. ;

Giopanou, Joanna ;

Spiropoulou, Nikolitsa ;

Harokopos, Vaggelis ;

Aidinis, Vassilis ;

Spyratos, Dionisios ;

Teliousi, Stamatia ;

Papadaki, Helen ;

Taraviras, Stavros ;

Snyder, Linda A. ;

Eickelberg, Oliver ;

Kardamakis, Dimitrios ;

Iwakura, Voichiro ;

Feyerabend, Thorsten B. ;

Rodewald, Hans-Reimer ;

Kalomenidis, Loannis ;

Blackwell, Timothy S. ;

Agalloti, Theodora ;

Stathopoulos, Georgios T. .

JOURNAL OF CLINICAL INVESTIGATION, 2015, 125 (06) :2317-2334

[18] Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth [J].

Grivennikov, Sergei I. ;

Wang, Kepeng ;

Mucida, Daniel ;

Stewart, C. Andrew ;

Schnabl, Bernd ;

Jauch, Dominik ;

Taniguchi, Koji ;

Yu, Guann-Yi ;

Oesterreicher, Christoph H. ;

Hung, Kenneth E. ;

Datz, Christian ;

Feng, Ying ;

Fearon, Eric R. ;

Oukka, Mohamed ;

Tessarollo, Lino ;

Coppola, Vincenzo ;

Yarovinsky, Felix ;

Cheroutre, Hilde ;

Eckmann, Lars ;

Trinchieri, Giorgio ;

Karin, Michael .

NATURE, 2012, 491 (7423) :254-+

[19] Interleukin-22 protects intestinal stem cells against genotoxic stress [J].

Gronke, Konrad ;

Hernandez, Pedro P. ;

Zimmermann, Jakob ;

Klose, Christoph S. N. ;

Kofoed-Branzk, Michael ;

Guendel, Fabian ;

Witkowski, Mario ;

Tizian, Caroline ;

Amann, Lukas ;

Schumacher, Fabian ;

Glatt, Hansruedi ;

Triantafyllopoulou, Antigoni ;

Diefenbach, Andreas .

NATURE, 2019, 566 (7743) :249-+

[20] Lymphotoxin β receptor mediates caspase-dependent tumor cell apoptosis in vitro and tumor suppression in vivo despite induction of NF-κB activation [J].

Hu, Xiaolin ;

Zimmerman, Mary A. ;

Bardhan, Kankana ;

Yang, Dafeng ;

Waller, Jennifer L. ;

Liles, Georgia B. ;

Lee, Jeffrey R. ;

Pollock, Raphael ;

Lev, Dina ;

Ware, Carl F. ;

Garber, Ellen ;

Bailly, Veronique ;

Browning, Jeffrey L. ;

Liu, Kebin .

CARCINOGENESIS, 2013, 34 (05) :1105-1114

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