IL22BP Mediates the Anti-Tumor Effects of Lymphotoxin Against Colorectal Tumors in Mice and Humans

TY - JOUR

T1 - IL22BP Mediates the Anti-Tumor Effects of Lymphotoxin Against Colorectal Tumors in Mice and Humans

AU - Kempski, Jan

AU - Giannou, Anastasios D

AU - Riecken, Kristoffer

AU - Zhao, Lilan

AU - Steglich, Babett

AU - Lücke, Jöran

AU - Garcia-Perez, Laura

AU - Karstens, Karl-Frederick

AU - Wöstemeier, Anna

AU - Nawrocki, Mikolaj

AU - Pelczar, Penelope

AU - Witkowski, Mario

AU - Nilsson, Sven

AU - Konczalla, Leonie

AU - Shiri, Ahmad Mustafa

AU - Kempska, Joanna

AU - Wahib, Ramez

AU - Brockmann, Leonie

AU - Huber, Philipp

AU - Gnirck, Ann-Christin

AU - Turner, Jan-Eric

AU - Zazara, Dimitra E

AU - Arck, Petra C

AU - Stein, Alexander

AU - Simon, Ronald

AU - Daubmann, Anne

AU - Meiners, Jan

AU - Perez, Daniel

AU - Strowig, Till

AU - Koni, Pandelakis

AU - Kruglov, Andrey A

AU - Sauter, Guido

AU - Izbicki, Jakob R

AU - Guse, Andreas H

AU - Roesch, Thomas

AU - Lohse, Ansgar W

AU - Flavell, Richard A

AU - Gagliani, Nicola

AU - Huber, Samuel

N1 - Jöran Lücke ist keine externe Person, sondern Mitarbeiter der I. Med. ZIM

PY - 2020/10

Y1 - 2020/10

N2 - 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 κB. 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.

AB - 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 κB. 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.

U2 - 10.1053/j.gastro.2020.06.033

DO - 10.1053/j.gastro.2020.06.033

M3 - SCORING: Journal article

C2 - 32585307

VL - 159

SP - 1417-1430.e3

JO - GASTROENTEROLOGY

JF - GASTROENTEROLOGY

SN - 0016-5085

IS - 4

ER -