Editorial

3 pages, 178 KiB

Open AccessEditorial

by Nabiha Yusuf

Int. J. Mol. Sci. 2023, 24(13), 10462; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241310462 - 21 Jun 2023

Cited by 1 | Viewed by 682

Skin cancer represents a major public health issue with a tremendous cost to healthcare systems in the United States and worldwide [...] Full article

(This article belongs to the Special Issue Immunomodulation of Skin Cancer)

Research

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18 pages, 6101 KiB

Open AccessArticle

A Predictive Model of Adaptive Resistance to BRAF/MEK Inhibitors in Melanoma

by Emmanuelle M. Ruiz, Solomon A. Alhassan, Youssef Errami, Zakaria Y. Abd Elmageed, Jennifer S. Fang, Guangdi Wang, Margaret A. Brooks, Joe A. Abi-Rached, Emad Kandil and Mourad Zerfaoui

Int. J. Mol. Sci. 2023, 24(9), 8407; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24098407 - 07 May 2023

Cited by 2 | Viewed by 1970

Abstract

The adaptive acquisition of resistance to BRAF and MEK inhibitor-based therapy is a common feature of melanoma cells and contributes to poor patient treatment outcomes. Leveraging insights from a proteomic study and publicly available transcriptomic data, we evaluated the predictive capacity of a [...] Read more.

The adaptive acquisition of resistance to BRAF and MEK inhibitor-based therapy is a common feature of melanoma cells and contributes to poor patient treatment outcomes. Leveraging insights from a proteomic study and publicly available transcriptomic data, we evaluated the predictive capacity of a gene panel corresponding to proteins differentially abundant between treatment-sensitive and treatment-resistant cell lines, deciphering predictors of treatment resistance and potential resistance mechanisms to BRAF/MEK inhibitor therapy in patient biopsy samples. From our analysis, a 13-gene signature panel, in both test and validation datasets, could identify treatment-resistant or progressed melanoma cases with an accuracy and sensitivity of over 70%. The dysregulation of HMOX1, ICAM, MMP2, and SPARC defined a BRAF/MEK treatment-resistant landscape, with resistant cases showing a >2-fold risk of expression of these genes. Furthermore, we utilized a combination of functional enrichment- and gene expression-derived scores to model and identify pathways, such as HMOX1-mediated mitochondrial stress response, as potential key drivers of the emergence of a BRAF/MEK inhibitor-resistant state in melanoma cells. Overall, our results highlight the utility of these genes in predicting treatment outcomes and the underlying mechanisms that can be targeted to reduce the development of resistance to BRAF/MEK targeted therapy. Full article

(This article belongs to the Special Issue Immunomodulation of Skin Cancer)

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22 pages, 3885 KiB

Open AccessArticle

Organogermanium THGP Induces Differentiation into M1 Macrophages and Suppresses the Proliferation of Melanoma Cells via Phagocytosis

by Junya Azumi, Tomoya Takeda, Yasuhiro Shimada, Tao Zhuang, Yoshihiko Tokuji, Naoya Sakamoto, Hisashi Aso and Takashi Nakamura

Int. J. Mol. Sci. 2023, 24(3), 1885; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24031885 - 18 Jan 2023

Cited by 5 | Viewed by 2043

Abstract

M1 macrophages are an important cell type related to tumor immunology and are known to phagocytose cancer cells. In previous studies, the organogermanium compound poly-trans-[(2-carboxyethyl)germasesquioxane] (Ge-132) and its hydrolysate, 3-(trihydroxygermyl) propanoic acid (THGP), have been reported to exert antitumor effects by [...] Read more.

M1 macrophages are an important cell type related to tumor immunology and are known to phagocytose cancer cells. In previous studies, the organogermanium compound poly-trans-[(2-carboxyethyl)germasesquioxane] (Ge-132) and its hydrolysate, 3-(trihydroxygermyl) propanoic acid (THGP), have been reported to exert antitumor effects by activating NK cells and macrophages through the induction of IFN-γ activity in vivo. However, the detailed molecular mechanism has not been clarified. In this study, we found that macrophages differentiate into the M1 phenotype via NF-κB activation under long-term culture in the presence of THGP in vitro and in vivo. Furthermore, long-term culture with THGP increases the ability of RAW 264.7 cells to suppress B16 4A5 melanoma cell proliferation. These mechanisms indicate that THGP promotes the M1 polarization of macrophages and suppresses the expression of signal-regulatory protein alpha (SIRP-α) in macrophages and CD47 in cancers. Based on these results, THGP may be considered a new regulatory reagent that suppresses tumor immunity. Full article

(This article belongs to the Special Issue Immunomodulation of Skin Cancer)

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15 pages, 4806 KiB

Open AccessArticle

Type I Interferons Enhance the Repair of Ultraviolet Radiation-Induced DNA Damage and Regulate Cutaneous Immune Suppression

by Mohammad Asif Sherwani, Israr Ahmad, Monica J. Lewis, Ahmed Abdelgawad, Harunur Rashid, Kevin Yang, Ching-Yi Chen, Chander Raman, Craig A. Elmets and Nabiha Yusuf

Int. J. Mol. Sci. 2022, 23(3), 1822; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031822 - 05 Feb 2022

Cited by 3 | Viewed by 2493

Abstract

Type I interferons (IFNs) are important enhancers of immune responses which are downregulated in human cancers, including skin cancer. Solar ultraviolet (UV) B radiation is a proven environmental carcinogen, and its exposure contributes to the high prevalence of skin cancer. The carcinogenic effects [...] Read more.

Type I interferons (IFNs) are important enhancers of immune responses which are downregulated in human cancers, including skin cancer. Solar ultraviolet (UV) B radiation is a proven environmental carcinogen, and its exposure contributes to the high prevalence of skin cancer. The carcinogenic effects of UV light can be attributed to the formation of cyclobutane pyrimidine dimers (CPD) and errors in the repair and replication of DNA. Treatment with a single dose of UVB (100 mJ/cm²) upregulated IFNα and IFNβ in the skin of C57BL/6 mice. IFNα and IFNβ were predominantly produced by CD11b+ cells. In mice lacking the type I IFN receptor 1 (IFNAR1), the repair of CPD following cutaneous exposure to a single dose of UVB (100 mJ/cm²) was decreased. UVB induced the expression of the DNA repair gene xeroderma pigmentosum A (XPA) in wild-type (WT) mice. In contrast, such treatment in IFNAR1 (IFNAR1-/-) mice downregulated XPA. A local UVB regimen consisting of UVB radiation (150 mJ/cm²) for 4 days followed by sensitization with hapten 2,4, dinitrofluorobenzene (DNFB) resulted in significant suppression of immune responses in both WT and IFNAR1-/- mice. However, there were significantly higher CD4+CD25+Foxp3+ regulatory T-cells in the draining lymph nodes of IFNAR1-/- mice in comparison to WT mice. Overall, our studies reveal a previously unknown action of type I IFNs in the repair of photodamage and the prevention of UVB-induced immune suppression. Full article

(This article belongs to the Special Issue Immunomodulation of Skin Cancer)

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Review

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23 pages, 1634 KiB

Open AccessReview

Enhancing Skin Cancer Immunotheranostics and Precision Medicine through Functionalized Nanomodulators and Nanosensors: Recent Development and Prospects

by Aisha Farhana

Int. J. Mol. Sci. 2023, 24(4), 3493; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043493 - 09 Feb 2023

Cited by 4 | Viewed by 2445

Abstract

Skin cancers, especially melanomas, present a formidable diagnostic and therapeutic challenge to the scientific community. Currently, the incidence of melanomas shows a high increase worldwide. Traditional therapeutics are limited to stalling or reversing malignant proliferation, increased metastasis, or rapid recurrence. Nonetheless, the advent [...] Read more.

Skin cancers, especially melanomas, present a formidable diagnostic and therapeutic challenge to the scientific community. Currently, the incidence of melanomas shows a high increase worldwide. Traditional therapeutics are limited to stalling or reversing malignant proliferation, increased metastasis, or rapid recurrence. Nonetheless, the advent of immunotherapy has led to a paradigm shift in treating skin cancers. Many state-of-art immunotherapeutic techniques, namely, active vaccination, chimeric antigen receptors, adoptive T-cell transfer, and immune checkpoint blockers, have achieved a considerable increase in survival rates. Despite its promising outcomes, current immunotherapy is still limited in its efficacy. Newer modalities are now being explored, and significant progress is made by integrating cancer immunotherapy with modular nanotechnology platforms to enhance its therapeutic efficacy and diagnostics. Research on targeting skin cancers with nanomaterial-based techniques has been much more recent than other cancers. Current investigations using nanomaterial-mediated targeting of nonmelanoma and melanoma cancers are directed at augmenting drug delivery and immunomodulation of skin cancers to induce a robust anticancer response and minimize toxic effects. Many novel nanomaterial formulations are being discovered, and clinical trials are underway to explore their efficacy in targeting skin cancers through functionalization or drug encapsulation. The focus of this review rivets on theranostic nanomaterials that can modulate immune mechanisms toward protective, therapeutic, or diagnostic approaches for skin cancers. The recent breakthroughs in nanomaterial-based immunotherapeutic modulation of skin cancer types and diagnostic potentials in personalized immunotherapies are discussed. Full article

(This article belongs to the Special Issue Immunomodulation of Skin Cancer)

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38 pages, 3727 KiB

Open AccessReview

Phytochemicals as Immunomodulatory Agents in Melanoma

by Claudio Tabolacci, Daniela De Vita, Antonio Facchiano, Giuseppina Bozzuto, Simone Beninati, Cristina Maria Failla, Marta Di Martile, Carla Lintas, Carlo Mischiati, Annarita Stringaro, Donatella Del Bufalo and Francesco Facchiano

Int. J. Mol. Sci. 2023, 24(3), 2657; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032657 - 31 Jan 2023

Cited by 3 | Viewed by 3139

Abstract

Cutaneous melanoma is an immunogenic highly heterogenic tumor characterized by poor outcomes when it is diagnosed late. Therefore, immunotherapy in combination with other anti-proliferative approaches is among the most effective weapons to control its growth and metastatic dissemination. Recently, a large amount of [...] Read more.

Cutaneous melanoma is an immunogenic highly heterogenic tumor characterized by poor outcomes when it is diagnosed late. Therefore, immunotherapy in combination with other anti-proliferative approaches is among the most effective weapons to control its growth and metastatic dissemination. Recently, a large amount of published reports indicate the interest of researchers and clinicians about plant secondary metabolites as potentially useful therapeutic tools due to their lower presence of side effects coupled with their high potency and efficacy. Published evidence was reported in most cases through in vitro studies but also, with a growing body of evidence, through in vivo investigations. Our aim was, therefore, to review the published studies focused on the most interesting phytochemicals whose immunomodulatory activities and/or mechanisms of actions were demonstrated and applied to melanoma models. Full article

(This article belongs to the Special Issue Immunomodulation of Skin Cancer)

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25 pages, 7901 KiB

Open AccessReview

Immunomodulation of Melanoma by Chemo-Thermo-Immunotherapy Using Conjugates of Melanogenesis Substrate NPrCAP and Magnetite Nanoparticles: A Review

by Yasuaki Tamura, Akira Ito, Kazumasa Wakamatsu, Takafumi Kamiya, Toshihiko Torigoe, Hiroyuki Honda, Toshiharu Yamashita, Hisashi Uhara, Shosuke Ito and Kowichi Jimbow

Int. J. Mol. Sci. 2022, 23(12), 6457; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126457 - 09 Jun 2022

Cited by 9 | Viewed by 2401

Abstract

A major advance in drug discovery and targeted therapy directed at cancer cells may be achieved by the exploitation and immunomodulation of their unique biological properties. This review summarizes our efforts to develop novel chemo-thermo-immunotherapy (CTI therapy) by conjugating a melanogenesis substrate, N [...] Read more.

A major advance in drug discovery and targeted therapy directed at cancer cells may be achieved by the exploitation and immunomodulation of their unique biological properties. This review summarizes our efforts to develop novel chemo-thermo-immunotherapy (CTI therapy) by conjugating a melanogenesis substrate, N-propionyl cysteaminylphenol (NPrCAP: amine analog of tyrosine), with magnetite nanoparticles (MNP). In our approach, NPrCAP provides a unique drug delivery system (DDS) because of its selective incorporation into melanoma cells. It also functions as a melanoma-targeted therapeutic drug because of its production of highly reactive free radicals (melanoma-targeted chemotherapy). Moreover, the utilization of MNP is a platform to develop thermo-immunotherapy because of heat shock protein (HSP) expression upon heat generation in MNP by exposure to an alternating magnetic field (AMF). This comprehensive review covers experimental in vivo and in vitro mouse melanoma models and preliminary clinical trials with a limited number of advanced melanoma patients. We also discuss the future directions of CTI therapy. Full article

(This article belongs to the Special Issue Immunomodulation of Skin Cancer)

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14 pages, 2569 KiB

Open AccessReview

Stromal Factors as a Target for Immunotherapy in Melanoma and Non-Melanoma Skin Cancers

by Taku Fujimura

Int. J. Mol. Sci. 2022, 23(7), 4044; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23074044 - 06 Apr 2022

Cited by 8 | Viewed by 2719

Abstract

Immune checkpoint inhibitors (ICIs), such as anti-programmed cell death 1 (PD1) antibodies (Abs) and anti-cytotoxic T-lymphocyte associated protein 4 (CTLA4) Abs, have been widely administered for not only advanced melanoma, but also various non-melanoma skin cancers. Since profiles of tumor-infiltrating leukocytes (TILs) play [...] Read more.

Immune checkpoint inhibitors (ICIs), such as anti-programmed cell death 1 (PD1) antibodies (Abs) and anti-cytotoxic T-lymphocyte associated protein 4 (CTLA4) Abs, have been widely administered for not only advanced melanoma, but also various non-melanoma skin cancers. Since profiles of tumor-infiltrating leukocytes (TILs) play important roles in immunotherapy using ICIs, it is important to evaluate cancer stromal cells such as tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), as well as stromal extracellular matrix protein, to predict the efficacy of ICIs. This review article focuses particularly on TAMs and related factors. Among TILs, TAMs and their related factors could be the optimal biomarkers for immunotherapy such as anti-PD1 Ab therapy. According to the studies presented, TAM-targeting therapies for advanced melanoma and non-melanoma skin cancer will develop in the future. Full article

(This article belongs to the Special Issue Immunomodulation of Skin Cancer)

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14 pages, 12293 KiB

Open AccessReview

Aetiology and Pathogenesis of Cutaneous Melanoma: Current Concepts and Advances

by Strahil Strashilov and Angel Yordanov

Int. J. Mol. Sci. 2021, 22(12), 6395; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126395 - 15 Jun 2021

Cited by 60 | Viewed by 9842

Abstract

Melanoma develops from malignant transformations of the pigment-producing melanocytes. If located in the basal layer of the skin epidermis, melanoma is referred to as cutaneous, which is more frequent. However, as melanocytes are be found in the eyes, ears, gastrointestinal tract, genitalia, urinary [...] Read more.

Melanoma develops from malignant transformations of the pigment-producing melanocytes. If located in the basal layer of the skin epidermis, melanoma is referred to as cutaneous, which is more frequent. However, as melanocytes are be found in the eyes, ears, gastrointestinal tract, genitalia, urinary system, and meninges, cases of mucosal melanoma or other types (e.g., ocular) may occur. The incidence and morbidity of cutaneous melanoma (cM) are constantly increasing worldwide. Australia and New Zealand are world leaders in this regard with a morbidity rate of 54/100,000 and a mortality rate of 5.6/100,000 for 2015. The aim of this review is to consolidate and present the data related to the aetiology and pathogenesis of cutaneous melanoma, thus rendering them easier to understand. In this article we will discuss these problems and the possible impacts on treatment for this disease. Full article

(This article belongs to the Special Issue Immunomodulation of Skin Cancer)

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