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Signal-Specific Transcription Factors Shaping the Tumor Immune Microenvironment

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (20 November 2021) | Viewed by 29711

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Special Issue Editor

Prof. Anna Maria Musti

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Guest Editor

Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
Interests: c-Jun/Ap-1 transcription factor; transcriptional regulation; signal transduction; cell death; cancer signaling; tumor microenvironment; GPER signaling

Special Issue Information

Dear Colleagues,

A growing number of evidence indicates that communication between tumor cells and the surrounding heterogeneous population of stromal cells is crucial for cancer progression and metastasis. In particular, both tumor cells and cancer-associated fibroblasts (CAFs) deregulate the immune-activity of tumor-infiltrating lymphocytes and macrophages, hence counteracting the anti-cancer immune response. Immunosuppressive traits of the tumor microenvironment (TME) are mainly induced by tumor cell surface immunomodulatory proteins (checkpoint proteins), along with various factors (cytokines, chemokines, growth-factors, etc.), metabolites and exosomal microRNA produced by either cancer cells or CAFs.

A major mechanism mediating the immunosuppressive effects of TME factors is the alteration of transcriptomic profiles associated with cytotoxic T–cell activation, Treg/Th1/Th17 balance and M1/M2 macrophage polarization. The transcriptional regulation of T cell fate or macrophage polarization is mediated by signal-inducible transcription factors (iTFs), which acts together with epigenetic histone modifications to define chromatin accessibility for lineage-specific TFs at specific enhancers. Conversely, the loss (or gain) of signal-specific iTFs in tumor-infiltrating immune cells may alter chromatin accessibility at specific enhancers, switching the original immune-activity of T cells or macrophages. Further elucidation of the TME signaling pathways affecting transcriptional regulation in tumor-infiltrating immune cells will certainly open new therapeutic roads, which may complement current checkpoint immunotherapy.

In this Special Issue of Cells, we invite contributors to submit original research articles or reviews leading to further insights into possible mechanisms linking TME signaling molecules, such as hormones and cytokines, to the cross-regulation between iTFs and chromatin modifiers shaping the cellular fate of tumor-infiltrating immune cells.

Prof. Anna Maria Musti
Guest Editor

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Keywords

tumor immunity
cancer-associated fibroblasts
tumor-infiltating immune cells
inducible transcription factors
chromatin accessibility
receptor signaling
signal transduction
T cell exhaustion
Th polarization
macrohage polarization
cytokines

Published Papers (5 papers)

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Research

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17 pages, 1826 KiB

Open AccessArticle

Modulating Tumor-Associated Macrophage Polarization by Synthetic and Natural PPARγ Ligands as a Potential Target in Breast Cancer

by Giulia Gionfriddo, Pierluigi Plastina, Giuseppina Augimeri, Stefania Catalano, Cinzia Giordano, Ines Barone, Catia Morelli, Francesca Giordano, Luca Gelsomino, Diego Sisci, Renger Witkamp, Sebastiano Andò, Klaske van Norren and Daniela Bonofiglio

Cells 2020, 9(1), 174; https://doi.org/10.3390/cells9010174 - 10 Jan 2020

Cited by 45 | Viewed by 6206

Abstract

Activation of peroxisome proliferator-activated receptor gamma (PPARγ) elicits anti-proliferative effects on different tumor cells, including those derived from breast cancer. PPARγ is also expressed in several cells of the breast tumor microenvironment, among which tumor associated macrophages (TAMs) play a pivotal role in tumor progression and metastasis. We explored the ability of synthetic and natural PPARγ ligands to modulate TAM polarization. The ligands included rosiglitazone (BRL-49653), and two docosahexaenoic acid (DHA) conjugates, N-docosahexaenoyl ethanolamine (DHEA) and N-docosahexaenoyl serotonin (DHA-5-HT). Human THP-1 monocytic cells were differentiated into M0, M1 and M2 macrophages that were characterized by qRT-PCR, ELISA and western blotting. A TAM-like phenotypic state was generated by adding two different breast cancer cell conditioned media (BCC-CM) to the cultures. Macrophages exposed to BCC-CM concomitantly exhibited M1 and M2 phenotypes. Interestingly, rosiglitazone, DHEA and DHA-5-HT attenuated cytokine secretion by TAMs, and this effect was reversed by the PPARγ antagonist GW9662. Given the key role played by PPARγ in the crosstalk between cancer cells and TAMs in tumor progression, its activation via endogenous or synthetic ligands may lead to novel strategies that target both epithelial neoplastic cells and the tumor microenvironment. Full article

(This article belongs to the Special Issue Signal-Specific Transcription Factors Shaping the Tumor Immune Microenvironment)

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Review

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22 pages, 1283 KiB

Open AccessReview

Dietary Fatty Acids at the Crossroad between Obesity and Colorectal Cancer: Fine Regulators of Adipose Tissue Homeostasis and Immune Response

by Manuela Del Cornò, Rosaria Varì, Beatrice Scazzocchio, Barbara Varano, Roberta Masella and Lucia Conti

Cells 2021, 10(7), 1738; https://doi.org/10.3390/cells10071738 - 09 Jul 2021

Cited by 7 | Viewed by 3132

Abstract

Colorectal cancer (CRC) is among the major threatening diseases worldwide, being the third most common cancer, and a leading cause of death, with a global incidence expected to increase in the coming years. Enhanced adiposity, particularly visceral fat, is a major risk factor for the development of several tumours, including CRC, and represents an important indicator of incidence, survival, prognosis, recurrence rates, and response to therapy. The obesity-associated low-grade chronic inflammation is thought to be a key determinant in CRC development, with the adipocytes and the adipose tissue (AT) playing a significant role in the integration of diet-related endocrine, metabolic, and inflammatory signals. Furthermore, AT infiltrating immune cells contribute to local and systemic inflammation by affecting immune and cancer cell functions through the release of soluble mediators. Among the factors introduced with diet and enriched in AT, fatty acids (FA) represent major players in inflammation and are able to deeply regulate AT homeostasis and immune cell function through gene expression regulation and by modulating the activity of several transcription factors (TF). This review summarizes human studies on the effects of dietary FA on AT homeostasis and immune cell functions, highlighting the molecular pathways and TF involved. The relevance of FA balance in linking diet, AT inflammation, and CRC is also discussed. Original and review articles were searched in PubMed without temporal limitation up to March 2021, by using fatty acid as a keyword in combination with diet, obesity, colorectal cancer, inflammation, adipose tissue, immune cells, and transcription factors. Full article

(This article belongs to the Special Issue Signal-Specific Transcription Factors Shaping the Tumor Immune Microenvironment)

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26 pages, 1600 KiB

Open AccessReview

The Multifaceted Output of c-Jun Biological Activity: Focus at the Junction of CD8 T Cell Activation and Exhaustion

by Athanasios G. Papavassiliou and Anna Maria Musti

Cells 2020, 9(11), 2470; https://doi.org/10.3390/cells9112470 - 13 Nov 2020

Cited by 54 | Viewed by 11109

Abstract

c-Jun is a major component of the dimeric transcription factor activator protein-1 (AP-1), a paradigm for transcriptional response to extracellular signaling, whose components are basic-Leucine Zipper (bZIP) transcription factors of the Jun, Fos, activating transcription factor (ATF), ATF-like (BATF) and Jun dimerization protein 2 (JDP2) gene families. Extracellular signals regulate c-Jun/AP-1 activity at multiple levels, including transcriptional and posttranscriptional regulation of c-Jun expression and transactivity, in turn, establishing the magnitude and the duration of c-Jun/AP-1 activation. Another important level of c-Jun/AP-1 regulation is due to the capability of Jun family members to bind DNA as a heterodimer with every other member of the AP-1 family, and to interact with other classes of transcription factors, thereby acquiring the potential to integrate diverse extrinsic and intrinsic signals into combinatorial regulation of gene expression. Here, we review how these features of c-Jun/AP-1 regulation underlie the multifaceted output of c-Jun biological activity, eliciting quite distinct cellular responses, such as neoplastic transformation, differentiation and apoptosis, in different cell types. In particular, we focus on the current understanding of the role of c-Jun/AP-1 in the response of CD8 T cells to acute infection and cancer. We highlight the transcriptional and epigenetic regulatory mechanisms through which c-Jun/AP-1 participates in the productive immune response of CD8 T cells, and how its downregulation may contribute to the dysfunctional state of tumor infiltrating CD8 T cells. Additionally, we discuss recent insights pointing at c-Jun as a suitable target for immunotherapy-based combination approaches to reinvigorate anti-tumor immune functions. Full article

(This article belongs to the Special Issue Signal-Specific Transcription Factors Shaping the Tumor Immune Microenvironment)

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Graphical abstract

15 pages, 1242 KiB

Open AccessReview

Signaling of Macrophages that Contours the Tumor Microenvironment for Promoting Cancer Development

by Justin K. Messex, Crystal J. Byrd and Geou-Yarh Liou

Cells 2020, 9(4), 919; https://doi.org/10.3390/cells9040919 - 09 Apr 2020

Cited by 13 | Viewed by 3472

Abstract

The immune response is critical in the maintenance of an organism’s health. The immune response can be broken down into two groups. The innate response, which is fast-acting and rids the body of most foreign material before infection occurs, and the adaptive response, a more specific defense against pathogen composed mostly of antibody production and killer cells. Linking the two responses via cytokine and chemokine secretion are macrophages, motile phagocytic cells that ingest and present foreign material playing a role in the innate and adaptive immune response. Although macrophages are necessary for the survival of an organism, studies have also shown macrophages play a more sinister role in the initiation, progression, and metastasis in tumorous cells. In this comprehensive review, we show how macrophages induce such a response through abnormal cellular signaling and creating a cellular microenvironment conducive for tumor growth and metastasis, as well as the future outlook of this field. Full article

(This article belongs to the Special Issue Signal-Specific Transcription Factors Shaping the Tumor Immune Microenvironment)

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14 pages, 1099 KiB

Open AccessReview

Pivotal Role of STAT3 in Shaping Glioblastoma Immune Microenvironment

by Christina Piperi, Kostas A. Papavassiliou and Athanasios G. Papavassiliou

Cells 2019, 8(11), 1398; https://doi.org/10.3390/cells8111398 - 06 Nov 2019

Cited by 73 | Viewed by 5004

Abstract

Glioblastoma belongs to the most malignant intracranial tumors characterized by indispensable growth and aggressiveness that highly associates with dismal prognosis and therapy resistance. Tumor heterogeneity that often challenges therapeutic schemes is largely attributed to the complex interaction of neoplastic cells with tumor microenvironment (TME). Soluble immunoregulatory molecules secreted by glioma cells attract astrocytes, circulating stem cells and a range of immune cells to TME, inducing a local production of cytokines, chemokines and growth factors that reprogram immune cells to inflammatory phenotypes and manipulate host’s immune response in favor of cancer growth and metastasis. Accumulating evidence indicates that these tolerogenic properties are highly regulated by the constitutive and persistent activation of the oncogenic signal transducer and activator of transcription 3 (STAT3) protein, which impairs anti-tumor immunity and enhances tumor progression. Herein, we discuss current experimental and clinical evidence that highlights the pivotal role of STAT3 in glioma tumorigenesis and particularly in shaping tumor immune microenvironment in an effort to justify the high need of selective targeting for glioma immunotherapy. Full article

(This article belongs to the Special Issue Signal-Specific Transcription Factors Shaping the Tumor Immune Microenvironment)

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