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17 pages, 7945 KiB

Open AccessArticle

Comparing T Cell Subsets in Broncho-Alveolar Lavage (BAL) and Peripheral Blood in Patients with Advanced Lung Cancer

by Annapaola Mariniello, Fabrizio Tabbò, Davide Indellicati, Martina Tesauro, Nicole Alessia Rezmives, Maria Lucia Reale, Angela Listì, Enrica Capelletto, Simona Carnio, Valentina Bertaglia, Caterina Mecca, Lorena Consito, Marco De Filippis, Maristella Bungaro, Chiara Paratore, Massimo Di Maio, Francesco Passiglia, Luisella Righi, Dario Sangiolo, Silvia Novello, Massimo Geuna and Paolo Bironzo Show full author list Hide full author list

Cells 2022, 11(20), 3226; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11203226 - 14 Oct 2022

Cited by 1 | Viewed by 1662

Abstract

Background: Lung cancer (LC) tissue for immunological characterization is often scarce. We explored and compared T cell characteristics between broncho-alveolar lavage from tumor affected (t-BAL) and contralateral lung (cl-BAL), with matched peripheral blood (PB). Methods: BAL and PB were collected during bronchoscopy for [...] Read more.

Background: Lung cancer (LC) tissue for immunological characterization is often scarce. We explored and compared T cell characteristics between broncho-alveolar lavage from tumor affected (t-BAL) and contralateral lung (cl-BAL), with matched peripheral blood (PB). Methods: BAL and PB were collected during bronchoscopy for diagnostic and/or therapeutic purposes in patients with monolateral primary lesion. Results: Of 33 patients undergoing BAL and PB sampling, 21 had histologically-confirmed LC. Most cases were locally-advanced or metastatic non-small cell LC. T cell characteristics were not significantly different in t-BAL vs. cl-BAL. Compared to PB, CD8 T cells in BAL presented features of immune activation and exhaustion (high PD-1, low IFN-g production). Accordingly, regulatory CD4 T cells were also higher in BAL vs. PB. When dichotomizing T cell density in t-BAL in high and low, we found that PD-L1 expression in LC was associated with T cell density in t-BAL. T-BAL with high T cell density had higher %IFN-g+CD8 T cells and lower %T-regs. Conclusion: In BAL from advanced LC patients, T cells present features of exhaustion. T cells in t-BAL could be the best surrogate of tumor-infiltrating T cell, and future studies should evaluate T cell phenotype and density as potential biomarkers for cancer immunotherapy outcome. Full article

(This article belongs to the Special Issue Mechanism of Anti-tumor Immunity of Cells and Immunotherapy)

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18 pages, 10166 KiB

Open AccessArticle

Combination of dl922-947 Oncolytic Adenovirus and G-Quadruplex Binders Uncovers Improved Antitumor Activity in Breast Cancer

by Fabiana Napolitano, Sarah Di Somma, Giuliano Castellano, Jussara Amato, Bruno Pagano, Antonio Randazzo, Giuseppe Portella and Anna Maria Malfitano

Cells 2022, 11(16), 2482; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11162482 - 10 Aug 2022

Cited by 5 | Viewed by 1956

Abstract

G-quadruplexes (G4s) are nucleic secondary structures characterized by G-tetrads. G4 motif stabilization induces DNA damage and cancer cell death; therefore, G4-targeting small molecules are the focus of clinical investigation. DNA destabilization induced by G4 ligands might potentiate the anticancer activity of agents targeting [...] Read more.

G-quadruplexes (G4s) are nucleic secondary structures characterized by G-tetrads. G4 motif stabilization induces DNA damage and cancer cell death; therefore, G4-targeting small molecules are the focus of clinical investigation. DNA destabilization induced by G4 ligands might potentiate the anticancer activity of agents targeting DNA or inhibiting its repair such as oncolytic viruses. This study represents the first approach combining G4 ligands, BRACO-19 (B19), pyridostatin (PDS), and the adenovirus dl922-947 in breast cancer cells. We demonstrated that G4 binders and dl922-947 induce cytotoxicity in breast cancer cells (MDA-MB-231 and MCF-7) and at higher doses in other neoplastic cell lines of thyroid (BHT-101 cells) and prostate (PC3 cells). G4 binders induce G4 motifs distributed in the S and G2/M phases in MCF-7 cells. G4 binder/dl922-947 combination increases cell cytotoxicity and the accumulation in subG0/G1. Indeed, G4 binders favor viral entry and replication with no effect on coxsackie and adenovirus receptor. Notably, dl922-947 induces G4 motifs and its combination with PDS potentiates this effect in MCF-7 cells. The agents alone or in combination similarly enhanced cell senescence. Additionally, PDS/dl922-947 combination inactivates STING signaling in MDA-MB-231 cells. Our results suggest that G4 binder/virotherapy combination may represent a novel therapeutic anticancer approach. Full article

(This article belongs to the Special Issue Mechanism of Anti-tumor Immunity of Cells and Immunotherapy)

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16 pages, 6395 KiB

Open AccessArticle

Combined TLR-3/TLR-8 Signaling in the Presence of α-Type-1 Cytokines Represents a Novel and Potent Dendritic Cell Type-1, Anti-Cancer Maturation Protocol

by Tadej Fevžer, Primož Poženel, Kaja Zajc, Nataša Tešić and Urban Švajger

Cells 2022, 11(5), 835; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11050835 - 28 Feb 2022

Cited by 2 | Viewed by 2466

Abstract

During the ex vivo generation of anti-cancer dendritic cell (DC)-based vaccines, their maturation still represents one of the most crucial steps of the manufacturing process. A superior DC vaccine should: possess extensive expression of co-stimulatory molecules, have an exceptional type-1 polarization capacity characterized [...] Read more.

During the ex vivo generation of anti-cancer dendritic cell (DC)-based vaccines, their maturation still represents one of the most crucial steps of the manufacturing process. A superior DC vaccine should: possess extensive expression of co-stimulatory molecules, have an exceptional type-1 polarization capacity characterized by their ability to produce IL-12p70 upon contact with responding T cells, migrate efficiently toward chemokine receptor 7 (CCR7) ligands, and have a superior capacity to activate cytotoxic T cell responses. A major advance has been achieved with the discovery of the next generation maturation protocol involving TLR-3 agonist (poly I:C), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, interferon (IFN)-γ, and IFN-α, and has since been known as α-type-1 maturation cocktail. We demonstrate how this combination can be greatly enhanced by the inclusion of a TLR-8 stimulation (R848), thereby contributing to potentiation between different TLR signaling pathways. For maximum efficiency, TLR-3 stimulation should precede (termed pre I:C) the stimulation with the R848/TNF-α/IL-1β/IFN-α/IFN-γ cocktail. When compared to DCs matured with α-type-1 maturation cocktail (αDCs), DCs matured with pre I:C/R848/TNF-α/IL-1β/IFN-α/IFN-γ (termed zDCs) displayed higher expression of CD80 and CD86 co-stimulatory molecules. Importantly, after CD40-ligand stimulation, which simulates DC-T cell contact, zDCs were much more proficient in IL-12p70 production. In comparison to αDCs, zDCs also displayed a significantly greater migratory capacity toward chemokine ligands (CCL)19 and CCL21, and had a significantly greater allo-stimulatory capacity. Finally, zDCs were also superior in their capacity to induce melanoma-specific CD8+ T cells, CD8+ T cell proliferation, and cytotoxic T cells, which produced approximately two times more IFN-γ and more granzyme B, than those stimulated with αDCs. In conclusion, we present a novel and superior DC maturation cocktail that could be easily implemented into next generation DC vaccine manufacturing protocols in future trials. Full article

(This article belongs to the Special Issue Mechanism of Anti-tumor Immunity of Cells and Immunotherapy)

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32 pages, 3234 KiB

Open AccessArticle

Identification of a Potent Cytotoxic Pyrazole with Anti-Breast Cancer Activity That Alters Multiple Pathways

by Denisse A. Gutierrez, Lisett Contreras, Paulina J. Villanueva, Edgar A. Borrego, Karla Morán-Santibañez, Jessica D. Hess, Rebecca DeJesus, Manuel Larragoity, Ana P. Betancourt, Jonathon E. Mohl, Elisa Robles-Escajeda, Khodeza Begum, Sourav Roy, Robert A. Kirken, Armando Varela-Ramirez and Renato J. Aguilera

Cells 2022, 11(2), 254; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11020254 - 12 Jan 2022

Cited by 7 | Viewed by 3192

Abstract

In this study, we identified a novel pyrazole-based derivative (P3C) that displayed potent cytotoxicity against 27 human cancer cell lines derived from different tissue origins with 50% cytotoxic concentrations (CC₅₀) in the low micromolar and nanomolar range, particularly in two triple-negative [...] Read more.

In this study, we identified a novel pyrazole-based derivative (P3C) that displayed potent cytotoxicity against 27 human cancer cell lines derived from different tissue origins with 50% cytotoxic concentrations (CC₅₀) in the low micromolar and nanomolar range, particularly in two triple-negative breast cancer (TNBC) cell lines (from 0.25 to 0.49 µM). In vitro assays revealed that P3C induces reactive oxygen species (ROS) accumulation leading to mitochondrial depolarization and caspase-3/7 and -8 activation, suggesting the participation of both the intrinsic and extrinsic apoptotic pathways. P3C caused microtubule disruption, phosphatidylserine externalization, PARP cleavage, DNA fragmentation, and cell cycle arrest on TNBC cells. In addition, P3C triggered dephosphorylation of CREB, p38, ERK, STAT3, and Fyn, and hyperphosphorylation of JNK and NF-kB in TNBC cells, indicating the inactivation of both p38MAPK/STAT3 and ERK1/2/CREB signaling pathways. In support of our in vitro assays, transcriptome analyses of two distinct TNBC cell lines (MDA-MB-231 and MDA-MB-468 cells) treated with P3C revealed 28 genes similarly affected by the treatment implicated in apoptosis, oxidative stress, protein kinase modulation, and microtubule stability. Full article

(This article belongs to the Special Issue Mechanism of Anti-tumor Immunity of Cells and Immunotherapy)

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13 pages, 1668 KiB

Open AccessArticle

N-Glycosylation Facilitates 4-1BB Membrane Localization by Avoiding Its Multimerization

by Ruoxuan Sun, Alyssa Min Jung Kim, Allison A. Murray and Seung-Oe Lim

Cells 2022, 11(1), 162; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11010162 - 4 Jan 2022

Cited by 6 | Viewed by 2638

Abstract

Leveraging the T cell immunity against tumors represents a revolutionary type of cancer therapy. 4-1BB is a well-characterized costimulatory immune receptor existing on activated T cells and mediating their proliferation and cytotoxicity under infectious diseases and cancers. Despite the accumulating interest in implementing [...] Read more.

Leveraging the T cell immunity against tumors represents a revolutionary type of cancer therapy. 4-1BB is a well-characterized costimulatory immune receptor existing on activated T cells and mediating their proliferation and cytotoxicity under infectious diseases and cancers. Despite the accumulating interest in implementing 4-1BB as a therapeutic target for immune-related disorders, less is known about the pattern of its intracellular behaviors and regulations. It has been previously demonstrated that 4-1BB is heavily modified by N-glycosylation; however, the biological importance of this modification lacks detailed elucidation. Through biochemical, biophysical, and cell-biological approaches, we systematically evaluated the impact of N-glycosylation on the ligand interaction, stability, and localization of 4-1BB. We hereby highlighted that N-glycan functions by preventing the oligomerization of 4-1BB, thus permitting its membrane transportation and fast turn-over. Without N-glycosylation, 4-1BB could be aberrantly accumulated intracellularly and fail to be sufficiently inserted in the membrane. The N-glycosylation-guided intracellular processing of 4-1BB serves as the potential mechanism explicitly modulating the “on” and “off” of 4-1BB through the control of protein abundance. Our study will further solidify the understanding of the biological properties of 4-1BB and facilitate the clinical practice against this promising therapeutic target. Full article

(This article belongs to the Special Issue Mechanism of Anti-tumor Immunity of Cells and Immunotherapy)

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8 pages, 1816 KiB

Open AccessArticle

A Unique Topoisomerase II Inhibitor with Dose-Affected Anticancer Mechanisms and Less Cardiotoxicity

by Zhi-Ying Li, Guang-Sen Xu and Xun Li

Cells 2021, 10(11), 3138; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10113138 - 12 Nov 2021

Cited by 2 | Viewed by 1959

Abstract

Type II DNA topoisomerase (topo II) is an essential nuclear enzyme and a well-validated anticancer drug target. Previously, we have carried out several rounds of structural optimizations on our in-house topo II inhibitor E17, which was shown to have superior anticancer activity [...] Read more.

Type II DNA topoisomerase (topo II) is an essential nuclear enzyme and a well-validated anticancer drug target. Previously, we have carried out several rounds of structural optimizations on our in-house topo II inhibitor E17, which was shown to have superior anticancer activity and less risk of multidrug resistance (MDR). Among the newly developed acridone derivatives, 6h displayed significant anticancer efficacy with unique mechanisms of action. At low concentrations, it arrested cancer cell cycles and triggered cell apoptosis, which is similar to the action of the well-known topo II inhibitor VP16. By contrast, 6h showed significant and long-term anti-proliferative activity at relatively high concentrations, with negligible influence on apoptosis. In addition, 6h exhibited no serious cardiotoxicity compared to doxorubicin (DOXO), a widely used topo II-targeting antineoplastic drug in clinic, but with damaging myocardial side effects. Collectively, our present work has supported the therapeutic value of 6h as a promising chemotherapy for cancers. Full article

(This article belongs to the Special Issue Mechanism of Anti-tumor Immunity of Cells and Immunotherapy)

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Review

Jump to: Research

17 pages, 745 KiB

Open AccessReview

On the Cutting Edge of Oral Cancer Prevention: Finding Risk-Predictive Markers in Precancerous Lesions by Longitudinal Studies

by Madeleine Crawford, Eliza H. Johnson, Kelly Y. P. Liu, Catherine Poh and Robert Y. L. Tsai

Cells 2022, 11(6), 1033; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11061033 - 18 Mar 2022

Cited by 5 | Viewed by 6187

Abstract

Early identification and management of precancerous lesions at high risk of developing cancers is the most effective and economical way to reduce the incidence, mortality, and morbidity of cancers as well as minimizing treatment-related complications, including pain, impaired functions, and disfiguration. Reliable cancer-risk-predictive [...] Read more.

Early identification and management of precancerous lesions at high risk of developing cancers is the most effective and economical way to reduce the incidence, mortality, and morbidity of cancers as well as minimizing treatment-related complications, including pain, impaired functions, and disfiguration. Reliable cancer-risk-predictive markers play an important role in enabling evidence-based decision making as well as providing mechanistic insight into the malignant conversion of precancerous lesions. The focus of this article is to review updates on markers that may predict the risk of oral premalignant lesions (OPLs) in developing into oral squamous cell carcinomas (OSCCs), which can logically be discovered only by prospective or retrospective longitudinal studies that analyze pre-progression OPL samples with long-term follow-up outcomes. These risk-predictive markers are different from those that prognosticate the survival outcome of cancers after they have been diagnosed and treated, or those that differentiate between different lesion types and stages. Up-to-date knowledge on cancer-risk-predictive markers discovered by longitudinally followed studies will be reviewed. The goal of this endeavor is to use this information as a starting point to address some key challenges limiting our progress in this area in the hope of achieving effective translation of research discoveries into new clinical interventions. Full article

(This article belongs to the Special Issue Mechanism of Anti-tumor Immunity of Cells and Immunotherapy)

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24 pages, 3777 KiB

Open AccessFeature PaperReview

The RAF Kinase Inhibitor Protein (RKIP): Good as Tumour Suppressor, Bad for the Heart

by Joshua Abd Alla and Ursula Quitterer

Cells 2022, 11(4), 654; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11040654 - 14 Feb 2022

Cited by 3 | Viewed by 3136

Abstract

The RAF kinase inhibitor protein, RKIP, is a dual inhibitor of the RAF1 kinase and the G protein-coupled receptor kinase 2, GRK2. By inhibition of the RAF1-MAPK (mitogen-activated protein kinase) pathway, RKIP acts as a beneficial tumour suppressor. By inhibition of GRK2, RKIP [...] Read more.

The RAF kinase inhibitor protein, RKIP, is a dual inhibitor of the RAF1 kinase and the G protein-coupled receptor kinase 2, GRK2. By inhibition of the RAF1-MAPK (mitogen-activated protein kinase) pathway, RKIP acts as a beneficial tumour suppressor. By inhibition of GRK2, RKIP counteracts GRK2-mediated desensitisation of G protein-coupled receptor (GPCR) signalling. GRK2 inhibition is considered to be cardioprotective under conditions of exaggerated GRK2 activity such as heart failure. However, cardioprotective GRK2 inhibition and pro-survival RAF1-MAPK pathway inhibition counteract each other, because inhibition of the pro-survival RAF1-MAPK cascade is detrimental for the heart. Therefore, the question arises, what is the net effect of these apparently divergent functions of RKIP in vivo? The available data show that, on one hand, GRK2 inhibition promotes cardioprotective signalling in isolated cardiomyocytes. On the other hand, inhibition of the pro-survival RAF1-MAPK pathway by RKIP deteriorates cardiomyocyte viability. In agreement with cardiotoxic effects, endogenous RKIP promotes cardiac fibrosis under conditions of cardiac stress, and transgenic RKIP induces heart dysfunction. Supported by next-generation sequencing (NGS) data of the RKIP-induced cardiac transcriptome, this review provides an overview of different RKIP functions and explains how beneficial GRK2 inhibition can go awry by RAF1-MAPK pathway inhibition. Based on RKIP studies, requirements for the development of a cardioprotective GRK2 inhibitor are deduced. Full article

(This article belongs to the Special Issue Mechanism of Anti-tumor Immunity of Cells and Immunotherapy)

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34 pages, 1391 KiB

Open AccessFeature PaperReview

Potential of E3 Ubiquitin Ligases in Cancer Immunity: Opportunities and Challenges

by Peng Ye, Xiaoxia Chi, Jong-Ho Cha, Shahang Luo, Guanghui Yang, Xiuwen Yan and Wen-Hao Yang

Cells 2021, 10(12), 3309; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10123309 - 25 Nov 2021

Cited by 26 | Viewed by 5537

Abstract

Cancer immunotherapies, including immune checkpoint inhibitors and immune pathway–targeted therapies, are promising clinical strategies for treating cancer. However, drug resistance and adverse reactions remain the main challenges for immunotherapy management. The future direction of immunotherapy is mainly to reduce side effects and improve [...] Read more.

Cancer immunotherapies, including immune checkpoint inhibitors and immune pathway–targeted therapies, are promising clinical strategies for treating cancer. However, drug resistance and adverse reactions remain the main challenges for immunotherapy management. The future direction of immunotherapy is mainly to reduce side effects and improve the treatment response rate by finding new targets and new methods of combination therapy. Ubiquitination plays a crucial role in regulating the degradation of immune checkpoints and the activation of immune-related pathways. Some drugs that target E3 ubiquitin ligases have exhibited beneficial effects in preclinical and clinical antitumor treatments. In this review, we discuss mechanisms through which E3 ligases regulate tumor immune checkpoints and immune-related pathways as well as the opportunities and challenges for integrating E3 ligases targeting drugs into cancer immunotherapy. Full article

(This article belongs to the Special Issue Mechanism of Anti-tumor Immunity of Cells and Immunotherapy)

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