Colorectal cancer cell-derived CCL20 recruits regulatory T cells to promote chemoresistance via FOXO1/CEBPB/NF-κB signaling

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Abstract

Background

Colorectal cancer (CRC) is one of the most common forms of cancer worldwide. The tumor microenvironment plays a key role in promoting the occurrence of chemoresistance in solid cancers. Effective targets to overcome resistance are necessary to improve the survival and prognosis of CRC patients. This study aimed to evaluate the molecular mechanisms of the tumor microenvironment that might be involved in chemoresistance in patients with CRC.

Methods

We evaluated the effects of CCL20 on chemoresistance of CRC by recruitment of regulatory T cells (Tregs) in vitro and in vivo.

Results

We found that the level of CCL20 derived from tumor cells was significantly higher in Folfox-resistant patients than in Folfox-sensitive patients. The high level of CCL20 was closely associated with chemoresistance and poor survival in CRC patients. Among the drugs in Folfox chemotherapy, we confirmed that 5-FU increased the expression of CCL20 in CRC. Moreover, CCL20 derived from 5-FU-resistant CRC cells promoted recruitment of Tregs. Tregs further enhanced the chemoresistance of CRC cells to 5-FU. FOXO1/CEBPB/NF-κB signaling was activated in CRC cells after 5-FU treatment and was required for CCL20 upregulation mediated by 5-FU. Furthermore, CCL20 blockade suppressed tumor progression and restored 5-FU sensitivity in CRC. Lastly, the expression of these signaling molecules mediating chemoresistance was closely correlated with poor survival of CRC patients.

Conclusions

CRC cell-secreted CCL20 can recruit Tregs to promote chemoresistance via FOXO1/CEBPB/NF-κB signaling, indicating that the FOXO1/CEBPB/NF-κB/CCL20 axis might provide a promising target for CRC treatment.

Electronic supplementary material

The online version of this article (10.1186/s40425-019-0701-2) contains supplementary material, which is available to authorized users.

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Most cited references 41

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FOXO transcription factors in cancer development and therapy.

Alexandra Coomans de Brachène, Jean-Baptiste Demoulin (2016)

The forkhead box O (FOXO) transcription factors are considered as tumor suppressors that limit cell proliferation and induce apoptosis. FOXO gene alterations have been described in a limited number of human cancers, such as rhabdomyosarcoma, leukemia and lymphoma. In addition, FOXO proteins are inactivated by major oncogenic signals such as the phosphatidylinositol-3 kinase pathway and MAP kinases. Their expression is also repressed by micro-RNAs in multiple cancer types. FOXOs are mediators of the tumor response to various therapies. However, paradoxical roles of FOXOs in cancer progression were recently described. FOXOs contribute to the maintenance of leukemia-initiating cells in acute and chronic myeloid leukemia. These factors may also promote invasion and metastasis of subsets of colon and breast cancers. Resistance to treatment was also ascribed to FOXO activation in multiple cases, including targeted therapies. In this review, we discuss the complex role of FOXOs in cancer development and response to therapy.

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Resistance to Antiangiogenic Therapy Is Associated with an Immunosuppressive Tumor Microenvironment in Metastatic Renal Cell Carcinoma.

Xian-De Liu, Anh Hoang, Lijun Zhou … (2015)

Renal cell carcinoma (RCC) is an immunogenic and proangiogenic cancer, and antiangiogenic therapy is the current mainstay of treatment. Patients with RCC develop innate or adaptive resistance to antiangiogenic therapy. There is a need to identify biomarkers that predict therapeutic resistance and guide combination therapy. We assessed the interaction between antiangiogenic therapy and the tumor immune microenvironment and determined their impact on clinical outcome. We found that antiangiogenic therapy-treated RCC primary tumors showed increased infiltration of CD4(+) and CD8(+) T lymphocytes, which was inversely related to patient overall survival and progression-free survival. Furthermore, specimens from patients treated with antiangiogenic therapy showed higher infiltration of CD4(+)FOXP3(+) regulatory T cells and enhanced expression of checkpoint ligand programed death-ligand 1 (PD-L1). Both immunosuppressive features were correlated with T-lymphocyte infiltration and were negatively related to patient survival. Treatment of RCC cell lines and RCC xenografts in immunodeficient mice with sunitinib also increased tumor PD-L1 expression. Results from this study indicate that antiangiogenic treatment may both positively and negatively regulate the tumor immune microenvironment. These findings generate hypotheses on resistance mechanisms to antiangiogenic therapy and will guide the development of combination therapy with PD-1/PD-L1-blocking agents.

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Cancer-cell-secreted CXCL11 promoted CD8 + T cells infiltration through docetaxel-induced-release of HMGB1 in NSCLC

Qun Gao, Shumin Wang, Xinfeng Chen … (2019)

Background Chemotherapy combined with immunotherapy becomes the main trend in lung cancer intervention; however, how chemotherapy promotes the immune function remains elusive. Therefore, we sought to determine how chemotherapy promotes the immune function. Methods We determined in 100 NSCLC patients the expression of CD8, functional markers (IFN-γ, Granzyme B, and Perforin) and specific chemokines by quantitative real-time reverse transcriptase-PCR. Functional experiments were carried out to check whether docetaxel (DOC), a chemotherapeutic agent, modifies the expression of HMGB1 and CXCL11, and influences the infiltration properties of CD8+ T cells to the tumor microenvironment. The mechanism of the release of HMGB1 and CXCL11 was determined by flow cytometry, immunofluorescence and western blotting. In in vivo experiment, we confirmed how DOC enhanced the recruitment of HER2-CAR T cells to tumor sites. Results We found that DOC upregulated the expression of chemokine receptor ligand CXCL11 in tumor microenvironment and subsequently enhanced CD8+ T cell recruitment. DOC treatment significantly increased HMGB1 release in an ROS-dependent manner. Recombinant protein HMGB1 stimulated the secretion of CXCL11 via NF-κB activation in vitro. Tumors from DOC-treated mice exhibited higher expression of HMGB1 and CXCL11, more HER2-CAR T cell infiltration, and reduced progression, relative to control. Increased HMGB1 and CXCL11 expressions were positively correlated with prolonged overall survival of lung cancer patients. Conclusions Our results demonstrate that DOC induces CD8+ T cell recruitment to the tumor microenvironment by enhancing the secretion of HMGB1 and CXCL11, thus improving the anti-tumor efficacy, indicating that modulating the HMGB1-CXCL11 axis might be helpful for NSCLC treatment. Electronic supplementary material The online version of this article (10.1186/s40425-019-0511-6) contains supplementary material, which is available to authorized users.

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Author and article information

Contributors

Yi Zhang:

ORCID: http://orcid.org/0000-0001-9861-4681

+86 371 66295320 , yizhang@zzu.edu.cn

Journal

Journal ID (nlm-ta): J Immunother Cancer

Journal ID (iso-abbrev): J Immunother Cancer

Title: Journal for Immunotherapy of Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 2051-1426

Publication date (Electronic): 8 August 2019

Publication date PMC-release: 8 August 2019

Publication date Collection: 2019

Volume: 7

Electronic Location Identifier: 215

Affiliations

[1 ]GRID grid.412633.1, Biotherapy Center, , The First Affiliated Hospital of Zhengzhou University, ; Zhengzhou, Henan 450052 People’s Republic of China

[2 ]GRID grid.412633.1, Cancer Center, , The First Affiliated Hospital of Zhengzhou University, ; Zhengzhou, Henan 450052 People’s Republic of China

[3 ]Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, Henan 450052 People’s Republic of China

[4 ]GRID grid.412633.1, Department of Anorectal Surgery, , The First Affiliated Hospital of Zhengzhou University, ; Zhengzhou, Henan 450052 People’s Republic of China

[5 ]ISNI 0000 0001 2189 3846, GRID grid.207374.5, School of Life Sciences, , Zhengzhou University, ; Zhengzhou, Henan 450001 People’s Republic of China

Author information

Yi Zhang http://orcid.org/0000-0001-9861-4681

Article

Publisher ID: 701

DOI: 10.1186/s40425-019-0701-2

PMC ID: 6688336

PubMed ID: 31395078

SO-VID: adef428a-508a-40c8-b395-fcc0fdce06a3

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 June 2019

Date accepted : 31 July 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: U1804281

Award ID: 81771781

Award ID: 81602024

Award Recipient : Yi Zhang

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Keywords: chemoresistance,ccl20,foxo1/cebpb/nf-κb,regulatory t cells,colorectal cancer (crc)

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Keywords: chemoresistance, ccl20, foxo1/cebpb/nf-κb, regulatory t cells, colorectal cancer (crc)

Colorectal cancer cell-derived CCL20 recruits regulatory T cells to promote chemoresistance via FOXO1/CEBPB/NF-κB signaling

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Regulatory T cell (Treg) therapy

Most cited references 41

FOXO transcription factors in cancer development and therapy.

Resistance to Antiangiogenic Therapy Is Associated with an Immunosuppressive Tumor Microenvironment in Metastatic Renal Cell Carcinoma.

Cancer-cell-secreted CXCL11 promoted CD8 + T cells infiltration through docetaxel-induced-release of HMGB1 in NSCLC

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