Research

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10 pages, 2125 KiB

Open AccessArticle

Cannabinoid Receptor Type-2 in B Cells Is Associated with Tumor Immunity in Melanoma

by Thomas Gruber, Steve Robatel, Mirela Kremenovic, Lukas Bäriswyl, Jürg Gertsch and Mirjam Schenk

Cancers 2021, 13(8), 1934; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13081934 - 16 Apr 2021

Cited by 5 | Viewed by 4307

Abstract

Agents targeting the endocannabinoid system (ECS) have gained attention as potential cancer treatments. Given recent evidence that cannabinoid receptor 2 (CB2R) regulates lymphocyte development and inflammation, we performed studies on CB2R in the immune response against melanoma. Analysis of The Cancer Genome Atlas [...] Read more.

Agents targeting the endocannabinoid system (ECS) have gained attention as potential cancer treatments. Given recent evidence that cannabinoid receptor 2 (CB2R) regulates lymphocyte development and inflammation, we performed studies on CB2R in the immune response against melanoma. Analysis of The Cancer Genome Atlas (TCGA) data revealed a strong positive correlation between CB2R expression and survival, as well as B cell infiltration in human melanoma. In a murine melanoma model, CB2R expression reduced the growth of melanoma as well as the B cell frequencies in the tumor microenvironment (TME), compared to CB2R-deficient mice. In depth analysis of tumor-infiltrating B cells using single-cell RNA sequencing suggested a less differentiated phenotype in tumors from Cb2r^−/− mice. Thus, in this study, we demonstrate for the first time a protective, B cell-mediated role of CB2R in melanoma. This gained insight might assist in the development of novel, CB2R-targeted cancer therapies. Full article

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

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22 pages, 6554 KiB

Open AccessArticle

NAMPT Over-Expression Recapitulates the BRAF Inhibitor Resistant Phenotype Plasticity in Melanoma

by Valentina Audrito, Vincenzo Gianluca Messana, Enrico Moiso, Nicoletta Vitale, Francesca Arruga, Lorenzo Brandimarte, Federica Gaudino, Elisa Pellegrino, Tiziana Vaisitti, Chiara Riganti, Roberto Piva and Silvia Deaglio

Cancers 2020, 12(12), 3855; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123855 - 20 Dec 2020

Cited by 16 | Viewed by 3149

Abstract

Serine–threonine protein kinase B-RAF (BRAF)-mutated metastatic melanoma (MM) is a highly aggressive type of skin cancer. Treatment of MM patients using BRAF/MEK inhibitors (BRAFi/MEKi) eventually leads to drug resistance, limiting any clinical benefit. Herein, we demonstrated that the nicotinamide adenine dinucleotide [...] Read more.

Serine–threonine protein kinase B-RAF (BRAF)-mutated metastatic melanoma (MM) is a highly aggressive type of skin cancer. Treatment of MM patients using BRAF/MEK inhibitors (BRAFi/MEKi) eventually leads to drug resistance, limiting any clinical benefit. Herein, we demonstrated that the nicotinamide adenine dinucleotide (NAD)-biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT) is a driving factor in BRAFi resistance development. Using stable and inducible NAMPT over-expression systems, we showed that forced NAMPT expression in MM BRAF-mutated cell lines led to increased energy production, MAPK activation, colony-formation capacity, and enhance tumorigenicity in vivo. Moreover, NAMPT over-expressing cells switched toward an invasive/mesenchymal phenotype, up-regulating expression of ZEB1 and TWIST, two transcription factors driving the epithelial to mesenchymal transition (EMT) process. Consistently, within the NAMPT-overexpressing cell line variants, we observed an increased percentage of a rare, drug-effluxing stem cell-like side population (SP) of cells, paralleled by up-regulation of ABCC1/MRP1 expression and CD133-positive cells. The direct correlation between NAMPT expression and gene set enrichments involving metastasis, invasiveness and mesenchymal/stemness properties were verified also in melanoma patients by analyzing The Cancer Genome Atlas (TCGA) datasets. On the other hand, CRISPR/Cas9 full knock-out NAMPT BRAFi-resistant MM cells are not viable, while inducible partial silencing drastically reduces tumor growth and aggressiveness. Overall, this work revealed that NAMPT over-expression is both necessary and sufficient to recapitulate the BRAFi-resistant phenotype plasticity. Full article

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

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19 pages, 2802 KiB

Open AccessArticle

Divergent Resistance Mechanisms to Immunotherapy Explain Responses in Different Skin Cancers

by Emmanuel Dollinger, Daniel Bergman, Peijie Zhou, Scott X. Atwood and Qing Nie

Cancers 2020, 12(10), 2946; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12102946 - 13 Oct 2020

Cited by 7 | Viewed by 2808

Abstract

The advent of immune checkpoint therapy for metastatic skin cancer has greatly improved patient survival. However, most skin cancer patients are refractory to checkpoint therapy, and furthermore, the intra-immune cell signaling driving response to checkpoint therapy remains uncharacterized. When comparing the immune transcriptome [...] Read more.

The advent of immune checkpoint therapy for metastatic skin cancer has greatly improved patient survival. However, most skin cancer patients are refractory to checkpoint therapy, and furthermore, the intra-immune cell signaling driving response to checkpoint therapy remains uncharacterized. When comparing the immune transcriptome in the tumor microenvironment of melanoma and basal cell carcinoma (BCC), we found that the presence of memory B cells and macrophages negatively correlate in both cancers when stratifying patients by their response, with memory B cells more present in responders. Moreover, inhibitory immune signaling mostly decreases in melanoma responders and increases in BCC responders. We further explored the relationships between macrophages, B cells and response to checkpoint therapy by developing a stochastic differential equation model which qualitatively agrees with the data analysis. Our model predicts BCC to be more refractory to checkpoint therapy than melanoma and predicts the best qualitative ratio of memory B cells and macrophages for successful treatment. Full article

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

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Review

Jump to: Research

16 pages, 1784 KiB

Open AccessReview

Review of the Molecular Genetics of Basal Cell Carcinoma; Inherited Susceptibility, Somatic Mutations, and Targeted Therapeutics

by James M. Kilgour, Justin L. Jia and Kavita Y. Sarin

Cancers 2021, 13(15), 3870; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13153870 - 31 Jul 2021

Cited by 11 | Viewed by 2983

Abstract

Basal cell carcinoma (BCC) is a significant public health concern, with more than 3 million cases occurring each year in the United States, and with an increasing incidence. The molecular basis of BCC is complex, involving an interplay of inherited genetic susceptibility, including [...] Read more.

Basal cell carcinoma (BCC) is a significant public health concern, with more than 3 million cases occurring each year in the United States, and with an increasing incidence. The molecular basis of BCC is complex, involving an interplay of inherited genetic susceptibility, including single nucleotide polymorphisms and genetic syndromes, and sporadic somatic mutations, often induced by carcinogenic exposure to UV radiation. This review outlines the currently known germline and somatic mutations implicated in the pathogenesis of BCC, including the key molecular pathways affected by these mutations, which drive oncogenesis. With advances in next generation sequencing and our understanding of the molecular genetics of BCC, established and emerging targeted therapeutics are offering new avenues for the non-surgical treatment of BCC. These agents, including Hedgehog pathway inhibitors, immune modulators, and histone deacetylase inhibitors, will also be discussed. Full article

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

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22 pages, 3756 KiB

Open AccessReview

Intersection of Two Checkpoints: Could Inhibiting the DNA Damage Response Checkpoint Rescue Immune Checkpoint-Refractory Cancer?

by Peter H. Goff, Rashmi Bhakuni, Thomas Pulliam, Jung Hyun Lee, Evan T. Hall and Paul Nghiem

Cancers 2021, 13(14), 3415; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13143415 - 08 Jul 2021

Cited by 15 | Viewed by 4078

Abstract

Metastatic cancers resistant to immunotherapy require novel management strategies. DNA damage response (DDR) proteins, including ATR (ataxia telangiectasia and Rad3-related), ATM (ataxia telangiectasia mutated) and DNA-PK (DNA-dependent protein kinase), have been promising therapeutic targets for decades. Specific, potent DDR inhibitors (DDRi) recently entered [...] Read more.

Metastatic cancers resistant to immunotherapy require novel management strategies. DNA damage response (DDR) proteins, including ATR (ataxia telangiectasia and Rad3-related), ATM (ataxia telangiectasia mutated) and DNA-PK (DNA-dependent protein kinase), have been promising therapeutic targets for decades. Specific, potent DDR inhibitors (DDRi) recently entered clinical trials. Surprisingly, preclinical studies have now indicated that DDRi may stimulate anti-tumor immunity to augment immunotherapy. The mechanisms governing how DDRi could promote anti-tumor immunity are not well understood; however, early evidence suggests that they can potentiate immunogenic cell death to recruit and activate antigen-presenting cells to prime an adaptive immune response. Merkel cell carcinoma (MCC) is well suited to test these concepts. It is inherently immunogenic as ~50% of patients with advanced MCC persistently benefit from immunotherapy, making MCC one of the most responsive solid tumors. As is typical of neuroendocrine cancers, dysfunction of p53 and Rb with upregulation of Myc leads to the very rapid growth of MCC. This suggests high replication stress and susceptibility to DDRi and DNA-damaging agents. Indeed, MCC tumors are particularly radiosensitive. Given its inherent immunogenicity, cell cycle checkpoint deficiencies and sensitivity to DNA damage, MCC may be ideal for testing whether targeting the intersection of the DDR checkpoint and the immune checkpoint could help patients with immunotherapy-refractory cancers. Full article

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

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14 pages, 1255 KiB

Open AccessReview

Methyltransferases in the Pathogenesis of Keratinocyte Cancers

by Eun Kyung Ko and Brian C. Capell

Cancers 2021, 13(14), 3402; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13143402 - 07 Jul 2021

Cited by 4 | Viewed by 2405

Abstract

Recent evidence suggests that the disruption of gene expression by alterations in DNA, RNA, and histone methylation may be critical contributors to the pathogenesis of keratinocyte cancers (KCs), made up of basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), which collectively [...] Read more.

Recent evidence suggests that the disruption of gene expression by alterations in DNA, RNA, and histone methylation may be critical contributors to the pathogenesis of keratinocyte cancers (KCs), made up of basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), which collectively outnumber all other human cancers combined. While it is clear that methylation modifiers are frequently dysregulated in KCs, the underlying molecular and mechanistic changes are only beginning to be understood. Intriguingly, it has recently emerged that there is extensive cross-talk amongst these distinct methylation processes. Here, we summarize and synthesize the latest findings in this space and highlight how these discoveries may uncover novel therapeutic approaches for these ubiquitous cancers. Full article

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

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13 pages, 4249 KiB

Open AccessReview

New Targeted Therapies and Immunotherapies for Locally Advanced Periocular Malignant Tumours: Towards a New ‘Eye-Sparing’ Paradigm?

by Arnaud Martel, Sandra Lassalle, Alexandra Picard-Gauci, Lauris Gastaud, Henri Montaudie, Corine Bertolotto, Sacha Nahon-Esteve, Gilles Poissonnet, Paul Hofman and Stephanie Baillif

Cancers 2021, 13(11), 2822; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112822 - 05 Jun 2021

Cited by 7 | Viewed by 3026

Abstract

The management of periocular skin malignant tumours is challenging. Surgery remains the mainstay of treatment for localised eyelid cancers. For more locally advanced cancers, especially those invading the orbit, orbital exenteration has long been considered the gold standard; however, it is a highly [...] Read more.

The management of periocular skin malignant tumours is challenging. Surgery remains the mainstay of treatment for localised eyelid cancers. For more locally advanced cancers, especially those invading the orbit, orbital exenteration has long been considered the gold standard; however, it is a highly disfiguring and traumatic surgery. The last two decades have been marked by the emergence of a new paradigm shift towards the use of ‘eye-sparing’ strategies. In the early 2000s, the first step consisted of performing wide conservative eyelid and orbital excisions. Multiple flaps and grafts were needed, as well as adjuvant radiotherapy in selected cases. Although being incredibly attractive, several limitations such as the inability to treat the more posteriorly located orbital lesions, as well as unbearable diplopia, eye pain and even secondary eye loss were identified. Therefore, surgeons should distinguish ‘eye-sparing’ from ‘sight-sparing’ strategies. The second step emerged over the last decade and was based on the development of targeted therapies and immunotherapies. Their advantages include their potential ability to treat almost all tumours, regardless of their locations, without performing complex surgeries. However, several limitations have been reported, including their side effects, the appearance of primary or secondary resistances, their price and the lack of consensus on treatment regimen and exact duration. The aim of this article was to review the evolution of the management of locally advanced periocular malignant tumours over the last three decades and highlight the new paradigm shift towards the use of ‘eye-sparing’ strategies. Full article

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

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25 pages, 959 KiB

Open AccessReview

Find the Flame: Predictive Biomarkers for Immunotherapy in Melanoma

by Mattia Garutti, Serena Bonin, Silvia Buriolla, Elisa Bertoli, Maria Antonietta Pizzichetta, Iris Zalaudek and Fabio Puglisi

Cancers 2021, 13(8), 1819; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13081819 - 10 Apr 2021

Cited by 16 | Viewed by 3364

Abstract

Immunotherapy has revolutionized the therapeutic landscape of melanoma. In particular, checkpoint inhibition has shown to increase long-term outcome, and, in some cases, it can be virtually curative. However, the absence of clinically validated predictive biomarkers is one of the major causes of unpredictable [...] Read more.

Immunotherapy has revolutionized the therapeutic landscape of melanoma. In particular, checkpoint inhibition has shown to increase long-term outcome, and, in some cases, it can be virtually curative. However, the absence of clinically validated predictive biomarkers is one of the major causes of unpredictable efficacy of immunotherapy. Indeed, the availability of predictive biomarkers could allow a better stratification of patients, suggesting which type of drugs should be used in a certain clinical context and guiding clinicians in escalating or de-escalating therapy. However, the difficulty in obtaining clinically useful predictive biomarkers reflects the deep complexity of tumor biology. Biomarkers can be classified as tumor-intrinsic biomarkers, microenvironment biomarkers, and systemic biomarkers. Herein we review the available literature to classify and describe predictive biomarkers for checkpoint inhibition in melanoma with the aim of helping clinicians in the decision-making process. We also performed a meta-analysis on the predictive value of PDL-1. Full article

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

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27 pages, 8655 KiB

Open AccessReview

Cutaneous Squamous Cell Carcinoma in the Age of Immunotherapy

by Yosuke Ishitsuka, Yuma Hanaoka, Atsushi Tanemura and Manabu Fujimoto

Cancers 2021, 13(5), 1148; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13051148 - 08 Mar 2021

Cited by 20 | Viewed by 4043

Abstract

Cutaneous squamous cell carcinoma (cSCC) is the second most prevalent skin cancer globally. Because most cSCC cases are manageable by local excision/radiotherapy and hardly become life-threatening, they are often excluded from cancer registries in most countries. Compared with cutaneous melanoma that originates from [...] Read more.

Cutaneous squamous cell carcinoma (cSCC) is the second most prevalent skin cancer globally. Because most cSCC cases are manageable by local excision/radiotherapy and hardly become life-threatening, they are often excluded from cancer registries in most countries. Compared with cutaneous melanoma that originates from the melanin-producing, neural crest-derived epidermal resident, keratinocyte (KC)-derived cancers are influenced by the immune system with regards to their pathogenetic behaviour. Congenital or acquired immunosurveillance impairments compromise tumoricidal activity and raises cSCC incidence rates. Intriguingly, expanded applications of programmed death-1 (PD-1) blockade therapies have revealed cSCC to be one of the most amenable targets, particularly when compared with the mucosal counterparts arisen in the esophagus or the cervix. The clinical observation reminds us that cutaneous tissue has a peculiarly high immunogenicity that can evoke tumoricidal recall responses topically. Here we attempt to redefine cSCC biology and review current knowledge about cSCC from multiple viewpoints that involve epidemiology, clinicopathology, molecular genetics, molecular immunology, and developmental biology. This synthesis not only underscores the primal importance of the immune system, rather than just a mere accumulation of ultraviolet-induced mutations but also reinforces the following hypothesis: PD-1 blockade effectively restores the immunity specially allowed to exist within the fully cornified squamous epithelium, that is, the epidermis. Full article

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

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12 pages, 267 KiB

Open AccessEditor’s ChoiceReview

Current Melanoma Treatments: Where Do We Stand?

by Alvaro Moreira, Lucie Heinzerling, Nina Bhardwaj and Philip Friedlander

Cancers 2021, 13(2), 221; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13020221 - 09 Jan 2021

Cited by 38 | Viewed by 4435

Abstract

Groundbreaking research in immunology and cancer biology in the last few decades has led to the discovery and development of novel therapeutics, such as immune checkpoint inhibitors and targeted therapies, which have revolutionized the clinical care of patients with metastatic melanoma. Updated data [...] Read more.

Groundbreaking research in immunology and cancer biology in the last few decades has led to the discovery and development of novel therapeutics, such as immune checkpoint inhibitors and targeted therapies, which have revolutionized the clinical care of patients with metastatic melanoma. Updated data from the largest clinical trials continue to support the use of these treatment modalities, both in the metastatic and in adjuvant settings, with studies showing the predicted plateau effect on survival curves. However, with growing evidence that neoadjuvant therapy is also associated with high rates of recurrence-free survival, the question about whether patients should receive adjuvant or neoadjuvant treatment raises new questions about therapeutic options. Finally, management after resistance and intervention with novel immunotherapies are newer challenges, particularly in the field of non-cutaneous melanoma. Full article

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

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