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Molecular Mechanisms and Therapeutic Modulation of Tumor Immune Microenvironment

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Special Issue Information
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Published Papers

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

Deadline for manuscript submissions: closed (15 June 2022) | Viewed by 22108

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Special Issue Editors

Dr. Suhwan Chang

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Guest Editor

College of Medicine, University of Ulsan, Ulsan 680-749, Korea
Interests: TNBC; PDAC; Tumor microenvironment; microRNA; RNA editing; Microbiome; Therapeutic agent

Dr. Mee-Hyun Lee

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Guest Editor

College of Korean Medicine, Dongshin University, Naju 520-714, Korea
Interests: molecular cancer targeted therapy; immunotherapy

Dr. Seokho Kim

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Guest Editor

Department of Medicinal Biotechnology, College of Health science, Dong-A University, Busan 49315, Korea
Interests: cancer immunotherapy

Special Issue Information

Dear Colleagues,

Transformed cells generated in our body are expected to be recognized and cleared by the immune system. To evade this defensive reaction, tumor cells employ several mechanisms, including: 1) removing or modulating cell surface molecules critical for recognition by immune cells, 2) inactivating antitumor immune cells by expressing inhibitory molecules, 3) modulating immune cell composition or state toward pro-tumorigenic condition by regulating stromal or endothelial cells, and 4) dampening the killing effect of immune cells by developing anti-apoptotic pathways. Some of these mechanisms are actively characterized and being applied into clinics. However, there is a considerable portion of patients not responding to current immunotherapy, and immunotherapeutic remission is also observed. Therefore, understanding the intricate communications between the tumor, immune, and other stromal cells is critical to overcome this limitation and provide novel insights for the development of novel immunotherapeutic agents.

This Special Issue aims to cover the diverse aspects of cancer immunotherapy in terms of molecular mechanisms and novel approaches for its clinical application. Original research articles or review papers are expected to focus on topics including but not limited to: (1) research on tumor–immune interaction between cancer, stroll, and immune cell factors, (2) the resistance mechanism of current immunotherapy and agents overcoming the limitation, (3) emerging regulators of tumor immunity, including the microbiome, diet, and other environmental stresses, and (4) cancer vaccine approaches using in vivo/vitro models.

Dr. Suhwan Chang
Dr. Mee-Hyun Lee
Dr. Seokho Kim
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

immunotherapy
tumor microenvironment
tumor microbiome
cancer vaccine
immune resistance model

Published Papers (6 papers)

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Research

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16 pages, 2841 KiB

Open AccessArticle

Phospho-Specific Flow Cytometry Reveals Signaling Heterogeneity in T-Cell Acute Lymphoblastic Leukemia Cell Lines

by Omar Perbellini, Chiara Cavallini, Roberto Chignola, Marilisa Galasso and Maria T. Scupoli

Cells 2022, 11(13), 2072; https://doi.org/10.3390/cells11132072 - 29 Jun 2022

Cited by 3 | Viewed by 2447

Abstract

Several signaling pathways are aberrantly activated in T-ALL due to genetic alterations of their components and in response to external microenvironmental cues. To functionally characterize elements of the signaling network in T-ALL, here we analyzed ten signaling proteins that are frequently altered in T-ALL -namely Akt, Erk1/2, JNK, Lck, NF-κB p65, p38, STAT3, STAT5, ZAP70, Rb- in Jurkat, CEM and MOLT4 cell lines, using phospho-specific flow cytometry. Phosphorylation statuses of signaling proteins were measured in the basal condition or under modulation with H₂O₂, PMA, CXCL12 or IL7. Signaling profiles are characterized by a high variability across the analyzed T-ALL cell lines. Hierarchical clustering analysis documents that higher intrinsic phosphorylation of Erk1/2, Lck, ZAP70, and Akt, together with ZAP70 phosphorylation induced by H₂O₂, identifies Jurkat cells. In contrast, CEM are characterized by higher intrinsic phosphorylation of JNK and Rb and higher responsiveness of Akt to external stimuli. MOLT4 cells are characterized by higher basal STAT3 phosphorylation. These data document that phospho-specific flow cytometry reveals a high variability in intrinsic as well as modulated signaling networks across different T-ALL cell lines. Characterizing signaling network profiles across individual leukemia could provide the basis to identify molecular targets for personalized T-ALL therapy. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapeutic Modulation of Tumor Immune Microenvironment)

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20 pages, 5787 KiB

Open AccessArticle

Scalable Enrichment of Immunomodulatory Human Acute Myeloid Leukemia Cell Line-Derived Extracellular Vesicles

by Heide-Marie Binder, Nicole Maeding, Martin Wolf, André Cronemberger Andrade, Balazs Vari, Linda Krisch, Fausto Gueths Gomes, Constantin Blöchl, Katharina Muigg, Rodolphe Poupardin, Anna M. Raninger, Thomas Heuser, Astrid Obermayer, Patricia Ebner-Peking, Lisa Pleyer, Richard Greil, Christian G. Huber, Katharina Schallmoser and Dirk Strunk

Cells 2021, 10(12), 3321; https://doi.org/10.3390/cells10123321 - 26 Nov 2021

Cited by 4 | Viewed by 3036

Abstract

Acute myeloid leukemia (AML) cells can secrete trophic factors, including extracellular vesicles (EVs), instructing the stromal leukemic niche. Here, we introduce a scalable workflow for purification of immunomodulatory AML-EVs to compare their phenotype and function to the parental AML cells and their secreted soluble factors. AML cell lines HL-60, KG-1, OCI-AML3, and MOLM-14 released EVs with a peak diameter of approximately 80 nm in serum-free particle-reduced medium. We enriched EVs >100x using tangential flow filtration (TFF) and separated AML-derived soluble factors and cells in parallel. EVs were characterized by electron microscopy, immunoblotting, and flow cytometry, confirming the double-membrane morphology, purity and identity. AML-EVs showed significant enrichment of immune response and leukemia-related pathways in tandem mass-tag proteomics and a significant dose-dependent inhibition of T cell proliferation, which was not observed with AML cells or their soluble factors. Furthermore, AML-EVs dose-dependently reduced NK cell lysis of third-party K-562 leukemia targets. This emphasizes the peculiar role of AML-EVs in leukemia immune escape and indicates novel EV-based targets for therapeutic interventions. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapeutic Modulation of Tumor Immune Microenvironment)

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14 pages, 6815 KiB

Open AccessArticle

siRNA Nanoparticle Targeting PD-L1 Activates Tumor Immunity and Abrogates Pancreatic Cancer Growth in Humanized Preclinical Model

by Jae Yun Jung, Hyun Jin Ryu, Seung-Hwan Lee, Dong-Young Kim, Myung Ji Kim, Eun Ji Lee, Yeon-Mi Ryu, Sang-Yeob Kim, Kyu-Pyo Kim, Eun Young Choi, Hyung Jun Ahn and Suhwan Chang

Cells 2021, 10(10), 2734; https://doi.org/10.3390/cells10102734 - 13 Oct 2021

Cited by 22 | Viewed by 3892

Abstract

Pancreatic cancer is characterized by late detection, frequent drug resistance, and a highly metastatic nature, leading to poor prognosis. Antibody-based immunotherapy showed limited success for pancreatic cancer, partly owing to the low delivery rate of the drug into the tumor. Herein, we describe a poly(lactic-co-glycolic acid;PLGA)-based siRNA nanoparticle targeting PD-L1 (siPD-L1@PLGA). The siPD-L1@PLGA exhibited efficient knockdown of PD-L1 in cancer cells, without affecting the cell viability up to 6 mg/mL. Further, 99.2% of PDAC cells uptake the nanoparticle and successfully blocked the IFN-gamma-mediated PD-L1 induction. Consistently, the siPD-L1@PLGA sensitized cancer cells to antigen-specific immune cells, as exemplified by Ovalbumin-targeting T cells. To evaluate its efficacy in vivo, we adopted a pancreatic PDX model in humanized mice, generated by grafting CD34⁺ hematopoeitic stem cells onto NSG mice. The siPD-L1@PLGA significantly suppressed pancreatic tumor growth in this model with upregulated IFN-gamma positive CD8 T cells, leading to more apoptotic tumor cells. Multiplex immunofluorescence analysis exhibited comparable immune cell compositions in control and siPD-L1@PLGA-treated tumors. However, we found higher Granzyme B expression in the siPD-L1@PLGA-treated tumors, suggesting higher activity of NK or cytotoxic T cells. Based on these results, we propose the application of siPD-L1@PLGA as an immunotherapeutic agent for pancreatic cancer. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapeutic Modulation of Tumor Immune Microenvironment)

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14 pages, 4849 KiB

Open AccessArticle

Inhibition of STAT3/PD-L1 and Activation of miR193a-5p Are Critically Involved in Apoptotic Effect of Compound K in Prostate Cancer Cells

by Jae-Hee Lee, Dae-Young Lee, Hyo-Jung Lee, Eunji Im, Deok-Yong Sim, Ji-Eon Park, Woon-Yi Park, Bum-Sang Shim and Sung-Hoon Kim

Cells 2021, 10(8), 2151; https://doi.org/10.3390/cells10082151 - 20 Aug 2021

Cited by 13 | Viewed by 3094

Abstract

Since the signal transducer and activator of transcription 3 (STAT3)/programmed death-ligand 1 (PD-L1) signaling plays an important role in tumor-immune microenvironments, in the present study, the role of STAT3/PD-L1 signaling in the apoptotic mechanism of an active ginseng saponin metabolite compound K (CK) was investigated in human prostate cancer cells. Here, CK exerted significant cytotoxicity without hurting RWPE1 normal prostate epithelial cells, increased sub-G1 and cleavage of Poly ADP-ribose polymerase (PARP) and attenuated the expression of pro-PARP and Pro-cysteine aspartyl-specific protease3 (pro-caspase-3) in LANCap, PC-3 and DU145 cells. Further, CK attenuated the expression of p-STAT3 and PD-L1 in DU145 cells along with disrupted the binding of STAT3 to PD-L1. Furthermore, CK effectively abrogated the expression of p-STAT3 and PD-L1 in interferon-gamma (INF-γ)-stimulated DU145cells. Additionally, CK suppressed the expression of vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), interleukin 6 (IL-6) and interleukin 10 (IL-10) as immune escape-related genes in DU145 cells. Likewise, as STAT3 targets genes, the expression of CyclinD1, c-Myc and B-cell lymphoma-extra-large (Bcl-xL) was attenuated in CK-treated DU145 cells. Notably, CK upregulated the expression of microRNA193a-5p (miR193a-5p) in DU145 cells. Consistently, miR193a-5p mimic suppressed p-STAT3, PD-L1 and pro-PARP, while miR193a-5p inhibitor reversed the ability of CK to attenuate the expression of p-STAT3, PD-L1 and pro-PARP in DU145 cells. Taken together, these findings support evidence that CK induces apoptosis via the activation of miR193a-5p and inhibition of PD-L1 and STAT3 signaling in prostate cancer cells. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapeutic Modulation of Tumor Immune Microenvironment)

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13 pages, 4245 KiB

Open AccessArticle

miR193a-5p Mediated ZNF746 and c-Myc Signaling Axis Is Critically Involved in Morusin Induced Apoptosis in Colorectal Cancer Cells

by Woon-Yi Park, Hyo-Jung Lee, Deok-Yong Sim, Eunji Im, Ji-Eon Park, Chi-Hoon Ahn, Bum-Sang Shim and Sung-Hoon Kim

Cells 2021, 10(8), 2065; https://doi.org/10.3390/cells10082065 - 12 Aug 2021

Cited by 5 | Viewed by 1978

Abstract

Novel target therapy is on the spotlight for effective cancer therapy. Hence, in the present study, the underlying apoptotic mechanism of Morusin was explored in association with miR193a-5p mediated ZNF746/c-Myc signaling axis in colorectal cancer cells (CRCs). Herein, Morusin reduced the viability and the number of colonies in HCT116 and SW480 CRCs. Additionally, Morusin increased sub-G1 population, cleavages of poly (ADP-ribose) polymerase (PARP) and caspase-3 and inhibited the expression of zinc finger protein 746 (ZNF746) and c-Myc in HCT116 and SW480 cells. Conversely, overexpression of ZNF746 suppressed the ability of Morusin to abrogate the expression of c-Myc in HCT116 cells, as ZNF746 enhanced the stability of c-Myc via their direct binding through nuclear colocalization in HCT116 cells by immunofluorescence and immunoprecipitation. Notably, Morusin upregulated miR193a-5p as a tumor suppressor, while miR193a-5p inhibitor masked the ability of Morusin to reduce the expression of ZNF746, c-Myc, and pro-PARP in HCT116 cells. To our knowledge, these findings provide the novel insight on miR193a-5p mediated inhibition of ZNF746/c-Myc signaling in Morusin induced apoptosis in CRCs. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapeutic Modulation of Tumor Immune Microenvironment)

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Review

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15 pages, 1429 KiB

Open AccessReview

Exosome as a Delivery Vehicle for Cancer Therapy

by Bohyun Moon and Suhwan Chang

Cells 2022, 11(3), 316; https://doi.org/10.3390/cells11030316 - 18 Jan 2022

Cited by 41 | Viewed by 6857

Abstract

Exosomes are small extracellular vesicles that are naturally produced and carry biomolecules such as proteins, microRNAs, and metabolites. Because of their small size and low level of biomolecule expression, the biological function of exosomes has only been identified recently. Despite the short history of investigation, exosomes seem to have remarkable potential as a delivery vehicle. With regards to cancer therapy, numerous antitumor agents demonstrate serious side effects (or toxicity), which has led to the unmet need for improving their selectivity and stability. Exosomes, either produced naturally or generated artificially, provide an attractive platform to load many types of molecules such as small molecules, biologics, and other therapeutic agents. Furthermore, the features of exosomes can be designed by selecting their source cells, or they can be engineered to incorporate affinity tags; thus, exosomes show promise as effective delivery vehicles for the complex tumor microenvironment. In this review, we focus on various exosomes produced from different cell types and their potential uses. Moreover, we summarize the current state of artificial exosomes as a drug carrier and provide an overview of the techniques used for their production. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapeutic Modulation of Tumor Immune Microenvironment)

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