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LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration.

ABSTRACT: Immune checkpoint blockade therapy has been successful in treating some types of cancer but has not shown clinical benefits for treating leukaemia1. This result suggests that leukaemia uses unique mechanisms to evade this therapy. Certain immune inhibitory receptors that are expressed by normal immune cells are also present on leukaemia cells. Whether these receptors can initiate immune-related primary signalling in tumour cells remains unknown. Here we use mouse models and human cells to show that LILRB4, an immunoreceptor tyrosine-based inhibition motif-containing receptor and a marker of monocytic leukaemia, supports tumour cell infiltration into tissues and suppresses T cell activity via a signalling pathway that involves APOE, LILRB4, SHP-2, uPAR and ARG1 in acute myeloid leukaemia (AML) cells. Deletion of LILRB4 or the use of antibodies to block LILRB4 signalling impeded AML development. Thus, LILRB4 orchestrates tumour invasion pathways in monocytic leukaemia cells by creating an immunosuppressive microenvironment. LILRB4 represents a compelling target for the treatment of monocytic AML.

SUBMITTER: Deng M

PROVIDER: S-EPMC6296374 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration.

Deng Mi M Gui Xun X Kim Jaehyup J Xie Li L Chen Weina W Li Zunling Z He Licai L Chen Yuanzhi Y Chen Heyu H Luo Weiguang W Lu Zhigang Z Xie Jingjing J Churchill Hywyn H Xu Yixiang Y Zhou Zhan Z Wu Guojin G Yu Chenyi C John Samuel S Hirayasu Kouyuki K Nguyen Nam N Liu Xiaoye X Huang Fangfang F Li Leike L Deng Hui H Tang Haidong H Sadek Ali H AH Zhang Lingbo L Huang Tao T Zou Yizhou Y Chen Benjamin B Zhu Hong H Arase Hisashi H Xia Ningshao N Jiang Youxing Y Collins Robert R You M James MJ Homsi Jade J Unni Nisha N Lewis Cheryl C Chen Guo-Qiang GQ Fu Yang-Xin YX Liao X Charlene XC An Zhiqiang Z Zheng Junke J Zhang Ningyan N Zhang Cheng Cheng CC

Nature 20181017 7728

Immune checkpoint blockade therapy has been successful in treating some types of cancer but has not shown clinical benefits for treating leukaemia<sup>1</sup>. This result suggests that leukaemia uses unique mechanisms to evade this therapy. Certain immune inhibitory receptors that are expressed by normal immune cells are also present on leukaemia cells. Whether these receptors can initiate immune-related primary signalling in tumour cells remains unknown. Here we use mouse models and human cell ...[more]

PMID: 30333625

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Project description:BackgroundCanonical WNT signalling plays a critical role in the regulation of ovarian development; mis-regulation of this key pathway in the adult ovary is associated with subfertility and tumourigenesis. The roles of Adenomatous polyposis coli 2 (APC2), a little-studied WNT signalling pathway regulator, in ovarian homeostasis, fertility and tumourigenesis have not previously been explored. Here, we demonstrate essential roles of APC2 in regulating ovarian WNT signalling and ovarian homeostasis.MethodsA detailed analysis of ovarian histology, gene expression, ovulation and hormone levels was carried out in 10 week old and in aged constitutive APC2-knockout (Apc2-/-) mice (mixed background). Statistical significance for qRT-PCR data was determined from 95% confidence intervals. Significance testing was performed using 2-tailed Student's t-test, when 2 experimental cohorts were compared. When more were compared, ANOVA test was used, followed by a post-hoc test (LSD or Games-Howell). P-values of < 0.05 were considered statistically significant.ResultsAPC2-deficiency resulted in activation of ovarian WNT signalling and sub-fertility driven by intra-ovarian defects. Follicular growth was perturbed, resulting in a reduced rate of ovulation and corpora lutea formation, which could not be rescued by administration of gonadotrophins. Defects in steroidogenesis and follicular vascularity contributed to the subfertility phenotype. Tumour incidence was assessed in aged APC2-deficient mice, which also carried a hypomorphic Apc allele. APC2-deficiency in these mice resulted in predisposition to granulosa cell tumour (GCT) formation, accompanied by acute tumour-associated WNT-signalling activation and a histologic pattern and molecular signature seen in human adult GCTs.ConclusionsOur work adds APC2 to the growing list of WNT-signalling members that regulate ovarian homeostasis, fertility and suppress GCT formation. Importantly, given that the APC2-deficient mouse develops tumours that recapitulate the molecular signature and histological features of human adult GCTs, this mouse has excellent potential as a pre-clinical model to study ovarian subfertility and transitioning to GCT, tumour biology and for therapeutic testing.

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LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration.

Publications

LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration.

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