The role of toll-like receptor 4 in tumor microenvironment

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Abstract

Tumors are closely related to chronic inflammation, during which there are various changes in inflammatory sites, such as immune cells infiltration, pro-inflammation cytokines production, and interaction between immune cells and tissue cells. Besides, substances, released from both tissue cells attacked by exogenous etiologies, also act on local cells. These changes induce a dynamic and complex microenvironment favorable for tumor growth, invasion, and metastasis. The toll-like receptor 4 (TLR4) is the first identified member of the toll-like receptor family that can recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular pattern (DAMPs). TLR4 expresses not only on immune cells but also on tumor cells. Accumulating evidences demonstrated that the activation of TLR4 in tumor microenvironment can not only boost the anti-tumor immunity but also give rise to immune surveillance and tumor progression. This review will summarize the expression and function of TLR4 on dendritic cells (DCs), tumor-associated macrophages (TAMs), T cells, myeloid-derived suppressor cells (MDSCs), tumor cells as well as stromal cells in tumor microenvironment. Validation of the multiple role of TLR4 in tumors could primarily pave the road for the development of anti-tumor immunotherapy.

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Subsets of myeloid-derived suppressor cells in tumor-bearing mice.

Je-In Youn, Srinivas Nagaraj, Michelle Collazo … (2008)

Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of cells that play a critical role in tumor associated immune suppression. In an attempt to identify a specific subset of MDSC primarily responsible for immunosuppressive features of these cells, 10 different tumor models were investigated. All models showed variable but significant increase in the population of MDSC. Variability of MDSC expansion in vivo matched closely the effect of tumor cell condition medium in vitro. MDSC consists of two major subsets of Ly6G(+)Ly6C(low) granulocytic and Ly6G(-)Ly6C(high) monocytic cells. Granulocytic MDSC have increased level of reactive oxygen species and undetectable level of NO whereas monocytic MDSC had increased level of NO but undetectable levels of reactive oxygen species. However, their suppressive activity per cell basis was comparable. Almost all tumor models demonstrated a preferential expansion of granulocytic subset of MDSC. We performed a phenotypical and functional analysis of several surface molecules previously suggested to be involved in MDSC-mediated suppression of T cells: CD115, CD124, CD80, PD-L1, and PD-L2. Although substantial proportion of MDSC expressed those molecules no differences in the level of their expression or the proportion, positive cells were found between MDSC and cells from tumor-free mice that lack immune suppressive activity. The level of MDSC-mediated T cell suppression did not depend on the expression of these molecules. These data indicate that suppressive features of MDSC is caused not by expansion of a specific subset but more likely represent a functional state of these cells.

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Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction.

K. Fitzgerald, E Palsson-McDermott, A. Bowie … (2001)

The recognition of microbial pathogens by the innate immune system involves Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns. Different TLRs recognize different pathogen-associated molecular patterns, with TLR-4 mediating the response to lipopolysaccharide from Gram-negative bacteria. All TLRs have a Toll/IL-1 receptor (TIR) domain, which is responsible for signal transduction. MyD88 is one such protein that contains a TIR domain. It acts as an adapter, being involved in TLR-2, TLR-4 and TLR-9 signalling; however, our understanding of how TLR-4 signals is incomplete. Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TIR-domain-containing protein in the human genome. Mal activates NF-kappaB, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2. Mal can form homodimers and can also form heterodimers with MyD88. Activation of NF-kappaB by Mal requires IRAK-2, but not IRAK, whereas MyD88 requires both IRAKs. Mal associates with IRAK-2 by means of its TIR domain. A dominant negative form of Mal inhibits NF-kappaB, which is activated by TLR-4 or lipopolysaccharide, but it does not inhibit NF-kappaB activation by IL-1RI or IL-18R. Mal associates with TLR-4. Mal is therefore an adapter in TLR-4 signal transduction.

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CD4 CTL, a Cytotoxic Subset of CD4+ T Cells, Their Differentiation and Function

Arata Takeuchi, Takashi Saito (2017)

CD4+ T cells with cytotoxic activity (CD4 CTL) have been observed in various immune responses. These cells are characterized by their ability to secrete granzyme B and perforin and to kill the target cells in an MHC class II-restricted fashion. Although CD4 CTLs were once thought to be an in vitro artifact associated with long-term culturing, they have since been identified in vivo and shown to play important roles in antiviral and antitumor immunity, as well as in inflammation. Functional characterization of CD4 CTL suggests their potential significance for therapeutic purposes. However, in order to develop effective CD4 CTL therapy it is necessary to understand the differentiation and generation of these cells. Although the mechanisms regulating development of various CD4+ Th subsets have been clarified in terms of the cytokine and transcription factor requirement, the CD4 CTL differentiation mechanism remains elusive. These cells are thought to be most closely related to Th1 cells secreting IFNγ and regulated by eomesodermin and/or T-bet transcription factors for their differentiation. However, our studies and those of others have identified CD4 CTLs within other CD4+ T cell subsets, including naïve T cells. We have identified class I-restricted T cell-associated molecule as a marker of CD4 CTL and, by using this marker, we detected a subset of naïve T cells that have the potential to differentiate into CD4 CTL. CD4 CTL develops at sites of infections as well as inflammation. In this review, we summarize recent findings about the generation of CD4 CTL and propose a model with several differentiation pathways.

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Author and article information

Journal

Journal ID (nlm-ta): Oncotarget

Journal ID (iso-abbrev): Oncotarget

Journal ID (publisher-id): Oncotarget

Journal ID (publisher-id): ImpactJ

Title: Oncotarget

Publisher: Impact Journals LLC

ISSN (Electronic): 1949-2553

Publication date Collection: 12 September 2017

Publication date (Electronic): 08 July 2017

Volume: 8

Issue: 39

Pages: 66656-66667

Affiliations

¹ Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China

² Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China

³ National Clinical Research Center for Cancer, Tianjin, China

⁴ Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

⁵ Tianjin’s Clinical Research Center for Cancer, Tianjin, China

⁶ Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China

Author notes

Correspondence to: Xiubao Ren, xiubaoren@ 123456163.com , rwziyi@ 123456yahoo.com

Article

Publisher ID: 19105

DOI: 10.18632/oncotarget.19105

PMC ID: 5630445

PubMed ID: 29029545

SO-VID: 6b1cc2c3-3f6e-4151-bd8f-447f1d06c346

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

The role of toll-like receptor 4 in tumor microenvironment

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Most cited references 84

Subsets of myeloid-derived suppressor cells in tumor-bearing mice.

Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction.

CD4 CTL, a Cytotoxic Subset of CD4+ T Cells, Their Differentiation and Function

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