Long non-coding RNA HOTTIP enhances IL-6 expression to potentiate immune escape of ovarian cancer cells by upregulating the expression of PD-L1 in neutrophils

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Abstract

Background

Long non-coding RNA (lncRNA) HOXA transcript at the distal tip (HOTTIP), has been demonstrated to be a vital biomarker when evaluating the prognosis of multiple cancers. Nevertheless, the potential function of HOTTIP in ovarian cancer (OC), a prevalent cancer among women worldwide, remains elusive. Hence, the current study aimed to elucidate the functional relevance of HOTTIP in the development of OC.

Methods

Positive expression of PD-L1 and IL-6 was determined using immunohistochemical staining in the collected OC and normal tissues. The correlation of IL-6 and PD-L1 was analyzed using flow cytometry, Western blot analysis as well as Pearson’s correlation coefficient. The interaction among HOTTIP, c-jun and IL-6 was investigated with the use of RIP, ChIP and dual luciferase reporter gene assays. Finally, the effects of HOTTIP on T cell proliferation and infiltration were identified through gain- and loss-of-function studies in vitro and in vivo.

Results

HOTTIP, IL-6 and PD-L1 were all highly expressed in OC tissues. A positive correlation was observed between IL-6 and PD-L1 and that between HOTTIP and IL-6 in OC tissues. HOTTIP was noted to promote the expression of IL-6 by binding to c-jun, which resulted in a promoted PD-L1 expression in neutrophils and immune escape while inhibiting T cell proliferation as well as tumor immunotherapy.

Conclusion

Taken together, our study unveiled that HOTTIP could promote the secretion of IL-6, and consequently up-regulate the expression of PD-L1 in neutrophils, thus inhibiting the activity of T cells and ultimately accelerating immune escape of OC cells. Our study provides a potential therapeutic strategy by targeting HOTTIP in OC.

Electronic supplementary material

The online version of this article (10.1186/s13046-019-1394-6) contains supplementary material, which is available to authorized users.

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Most cited references 19

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IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer

K Abiko, N Matsumura, J Hamanishi … (2015)

Background: PD-L1 (programmed cell death 1 ligand 1) on tumour cells suppresses host immunity through binding to its receptor PD-1 on lymphocytes, and promotes peritoneal dissemination in mouse models of ovarian cancer. However, how PD-L1 expression is regulated in ovarian cancer microenvironment remains unclear. Methods: The number of CD8-positive lymphocytes and PD-L1 expression in tumour cells was assessed in ovarian cancer clinical samples. PD-L1 expression and tumour progression in mouse models under conditions of altering IFN-γ signals was assessed. Results: The number of CD8-positive cells in cancer stroma was very high in peritoneally disseminated tumours, and was strongly correlated to PD-L1 expression on the tumour cells (P<0.001). In mouse models, depleting IFNGR1 (interferon-γ receptor 1) resulted in lower level of PD-L1 expression in tumour cells, increased the number of tumour-infiltrating CD8-positive lymphocytes, inhibition of peritoneal disseminated tumour growth and longer survival (P=0.02). The injection of IFN-γ into subcutaneous tumours induced PD-L1 expression and promoted tumour growth, and PD-L1 depletion completely abrogated tumour growth caused by IFN-γ injection (P=0.01). Conclusions: Interferon-γ secreted by CD8-positive lymphocytes upregulates PD-L1 on ovarian cancer cells and promotes tumour growth. The lymphocyte infiltration and the IFN-γ status may be the key to effective anti-PD-1 or anti-PD-L1 therapy in ovarian cancer.

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IL-17 can promote tumor growth through an IL-6–Stat3 signaling pathway

Lin Wang, Tangsheng Yi, Marcin Kortylewski … (2009)

Although the Th17 subset and its signature cytokine, interleukin (IL)-17A (IL-17), are implicated in certain autoimmune diseases, their role in cancer remains to be further explored. IL-17 has been shown to be elevated in several types of cancer, but how it might contribute to tumor growth is still unclear. We show that growth of B16 melanoma and MB49 bladder carcinoma is reduced in IL-17−/− mice but drastically accelerated in IFN-γ−/− mice, contributed to by elevated intratumoral IL-17, indicating a role of IL-17 in promoting tumor growth. Adoptive transfer studies and analysis of the tumor microenvironment suggest that CD4+ T cells are the predominant source of IL-17. Enhancement of tumor growth by IL-17 involves direct effects on tumor cells and tumor-associated stromal cells, which bear IL-17 receptors. IL-17 induces IL-6 production, which in turn activates oncogenic signal transducer and activator of transcription (Stat) 3, up-regulating prosurvival and proangiogenic genes. The Th17 response can thus promote tumor growth, in part via an IL-6–Stat3 pathway.

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Tumour-activated neutrophils in gastric cancer foster immune suppression and disease progression through GM-CSF-PD-L1 pathway

Ting-ting Wang, Yong-liang Zhao, Liu-sheng Peng … (2017)

Objective Neutrophils are prominent components of solid tumours and exhibit distinct phenotypes in different tumour microenvironments. However, the nature, regulation, function and clinical relevance of neutrophils in human gastric cancer (GC) are presently unknown. Design Flow cytometry analyses were performed to examine levels and phenotype of neutrophils in samples from 105 patients with GC. Kaplan-Meier plots for overall survival were performed using the log-rank test. Neutrophils and T cells were isolated, stimulated and/or cultured for in vitro and in vivo regulation and function assays. Results Patients with GC showed a significantly higher neutrophil infiltration in tumours. These tumour-infiltrating neutrophils showed an activated CD54+ phenotype and expressed high level immunosuppressive molecule programmed death-ligand 1 (PD-L1). Neutrophils activated by tumours prolonged their lifespan and strongly expressed PD-L1 proteins with similar phenotype to their status in GC, and significant correlations were found between the levels of PD-L1 and CD54 on tumour-infiltrating neutrophils. Moreover, these PD-L1+ neutrophils in tumours were associated with disease progression and reduced GC patient survival. Tumour-derived GM-CSF activated neutrophils and induced neutrophil PD-L1 expression via Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) signalling pathway. The activated PD-L1+ neutrophils effectively suppressed normal T-cell immunity in vitro and contributed to the growth and progression of human GC in vivo; the effect could be reversed by blocking PD-L1 on these neutrophils. Conclusions Our results illuminate a novel mechanism of PD-L1 expression on tumour-activated neutrophils in GC, and also provide functional evidence for these novel GM-CSF-PD-L1 pathways to prevent, and to treat this immune tolerance feature of GC.

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Author and article information

Contributors

Anquan Shang: shanganquan@tongji.edu.cn

Weiwei Wang: wangweiweiiw@126.com

Chenzheng Gu: guchenzheng@tongji.edu.cn

Chen Chen: olivia_chan@tongji.edu.cn

Bingjie Zeng: better_zbj@tongji.edu.cn

Yibao Yang: yangyibao@tongji.edu.cn

Ping Ji: 1610634@tongji.edu.cn

Junjun Sun: sunjunjun@tongji.edu.cn

Junlu Wu: wujunlu@tongji.edu.cn

Wenying Lu: luwenying2007@126.com

Zujun Sun: +86-021-66111751 , sunzujun@tongji.edu.cn

Dong Li: +86-021-66111751 , lidong@tongji.edu.cn

Journal

Journal ID (nlm-ta): J Exp Clin Cancer Res

Journal ID (iso-abbrev): J. Exp. Clin. Cancer Res

Title: Journal of Experimental & Clinical Cancer Research : CR

Publisher: BioMed Central (London )

ISSN (Print): 0392-9078

ISSN (Electronic): 1756-9966

Publication date (Electronic): 18 September 2019

Publication date PMC-release: 18 September 2019

Publication date Collection: 2019

Volume: 38

Electronic Location Identifier: 411

Affiliations

[1 ]ISNI 0000 0004 1799 5032, GRID grid.412793.a, Department of Laboratory Medicine, , Tongji Hospital of Tongji University School of Medicine, ; 389 Xincun Road, Shanghai, 200065 China

[2 ]Department of Pathology, The Sixth People’s Hospital of Yancheng City, Yancheng, 224001 China

Article

Publisher ID: 1394

DOI: 10.1186/s13046-019-1394-6

PMC ID: 6751824

PubMed ID: 31533774

SO-VID: 398055b5-42ea-401a-9daa-aa3b1fac4e8b

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 23 April 2019

Date accepted : 26 August 2019

Funding

Funded by: the National Natural Science Foundation of China

Award ID: 81802084, 81873975

Award Recipient : Zujun Sun

Funded by: the Excellent Academic Leader Training Program of Shanghai Health System

Award ID: 2018BR31

Award Recipient : Zujun Sun

Funded by: the Medical Guidance Science and Technology Support Project of Shanghai

Award ID: 19411964800

Award Recipient : Zujun Sun

Funded by: the Natural Science Foundation of Shanghai

Award ID: 19ZR1448800

Award Recipient : Zujun Sun

Funded by: the Clinical Research and Cultivation Project of Shanghai Tongji Hospital

Award ID: ITJ(ZD)1803, ITJ(ZD)1905, ITJ(QN)1905

Award Recipient : Zujun Sun

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: ovarian cancer,neutrophils,interleukin-6,programmed death-ligand 1,hoxa transcript at the distal tip,immune escape

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: ovarian cancer, neutrophils, interleukin-6, programmed death-ligand 1, hoxa transcript at the distal tip, immune escape

Long non-coding RNA HOTTIP enhances IL-6 expression to potentiate immune escape of ovarian cancer cells by upregulating the expression of PD-L1 in neutrophils

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Abstract

Background

Methods

Results

Conclusion

Electronic supplementary material

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Karger: Oncology

Most cited references 19

IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer

IL-17 can promote tumor growth through an IL-6–Stat3 signaling pathway

Tumour-activated neutrophils in gastric cancer foster immune suppression and disease progression through GM-CSF-PD-L1 pathway

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