Direct Interaction of CD40 on Tumor Cells with CD40L on T Cells Increases the Proliferation of Tumor Cells by Enhancing TGF-β Production and Th17 Differentiation

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Abstract

It has recently been reported that the CD40-CD40 ligand (CD40L) interaction is important in Th17 development. In addition, transforming growth factor—beta (TGF-β) promotes tumorigenesis as an immunosuppressive cytokine and is crucial in the development of Th17 cells. This study investigated the role of CD40 in breast cancer cells and its role in immunosuppressive function and tumor progression. CD40 was highly expressed in the breast cancer cell line MDA-MB231, and its stimulation with CD40 antibodies caused the up-regulation of TGF-β. Direct CD40-CD40L interaction between MDA-MB231 cells and activated T cells also increased TGF-β production and induced the production of IL-17, which accelerated the proliferation of MDA-MB231 cells through the activation of STAT3. Taken together, the direct CD40-CD40L interaction of breast tumor cells and activated T cells increases TGF-β production and the differentiation of Th17 cells, which promotes the proliferation of breast cancer cells.

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Most cited references 52

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T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions.

S. P. Schoenberger, R Toes, E van der Voort … (1998)

Although in vivo priming of CD8+ cytotoxic T lymphocytes (CTLs) generally requires the participation of CD4+ T-helper lymphocytes, the nature of the 'help' provided to CTLs is unknown. One widely held view is that help for CTLs is mediated by cytokines produced by T-helper cells activated in proximity to the CTL precursor at the surface of an antigen-presenting cell (APC). An alternative theory is that, rather than being directly supplied to the CTL by the helper cell, help is delivered through activation of the APC, which can then prime the CTL directly. CD40 and its ligand, CD40L, may activate the APC to allow CTL priming. CD40L is expressed on the surface of activated CD4+ T-helper cells and is involved in their activation and in the development of their effector functions. Ligation of CD40 on the surface of APCs such as dendritic cells, macrophages and B cells greatly increases their antigen-presentation and co-stimulatory capacity. Here we report that signalling through CD40 can replace CD4+ T-helper cells in priming of helper-dependent CD8+ CTL responses. Blockade of CD40L inhibits CTL priming; this inhibition is overcome by signalling through CD40. CD40-CD40L interactions are therefore vital in the delivery of T-cell help for CTL priming.

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Roles of TGFbeta in metastasis.

David Padua, Joan Massagué (2009)

The TGFbeta signaling pathway is conserved from flies to humans and has been shown to regulate such diverse processes as cell proliferation, differentiation, motility, adhesion, organization, and programmed cell death. Both in vitro and in vivo experiments suggest that TGFbeta can utilize these varied programs to promote cancer metastasis through its effects on the tumor microenvironment, enhanced invasive properties, and inhibition of immune cell function. Recent clinical evidence demonstrating a link between TGFbeta signaling and cancer progression is fostering interest in this signaling pathway as a therapeutic target. Anti-TGFbeta therapies are currently being developed and tested in pre-clinical studies. However, targeting TGFbeta carries a substantial risk as this pathway is implicated in multiple homeostatic processes and is also known to have tumor-suppressor functions. Additionally, clinical and experimental results show that TGFbeta has diverse and often conflicting roles in tumor progression even within the same tumor types. The development of TGFbeta inhibitors for clinical use will require a deeper understanding of TGFbeta signaling, its consequences, and the contexts in which it acts.

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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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Author and article information

Contributors

Aamir Ahmad: Role: Academic Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 18 May 2015

Publication date Collection: 2015

Volume: 10

Issue: 5

Electronic Location Identifier: e0125742

Affiliations

[1 ]Laboratory of Vitamin C and Antioxidant Immunology, Department of Anatomy, Seoul National University College of Medicine, Seoul, 110–799, Korea

[2 ]Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, 110–799, Korea

Wayne State University School of Medicine, UNITED STATES

Author notes

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: JSK. Performed the experiments: HK YK SB JMK. Analyzed the data: YH WJL JSK. Contributed reagents/materials/analysis tools: Jiwon Choi JMH MJ Jiyea Choi. Wrote the paper: HK JSK.

* E-mail: genius29@ 123456snu.ac.kr

Article

Publisher ID: PONE-D-14-45275

DOI: 10.1371/journal.pone.0125742

PMC ID: 4436336

PubMed ID: 25992978

SO-VID: 9b9e158d-9a26-46df-9e7e-acb68bfdc6ad

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This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

History

Date received : 27 October 2014

Date accepted : 26 March 2015

Page count

Figures: 5, Tables: 0, Pages: 17

Funding

Grant from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (#1020030).

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Data Availability All relevant data are within the paper and its Supporting Information files.

Direct Interaction of CD40 on Tumor Cells with CD40L on T Cells Increases the Proliferation of Tumor Cells by Enhancing TGF-β Production and Th17 Differentiation

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Most cited references 52

T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions.

Roles of TGFbeta in metastasis.

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

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