Malignant melanoma, one of the most aggressive human malignancies, is responsible for 80% of skin cancer deaths. Whilst early detection of disease progression or metastasis can improve patient survival, this remains a challenge due to the lack of reliable biomarkers. Importantly, these clinical challenges are not unique to humans, as melanoma affects many other species, including companion animals, such as the dog and horse. Extracellular vesicles (EVs) are tiny nanoparticles involved in cell-to-cell communication. Several protein and genomic EV markers have been described in the literature, as well as a wide variety of methods for isolating EVs from body fluids. As such, they may be valuable biomarkers in cancer and may address some clinical challenges in the management melanoma. This review aimed to explore the translational applications of EVs as biomarkers in melanoma, as well as their role in the clinical setting in humans and animals. A summary of melanoma-specific protein and genomic EV markers is presented, followed by a discussion of the role EVs in monitoring disease progression and treatment response. Finally, herein, we reviewed the advantages and disadvantages of methods utilised to isolate EVs from bodily fluids in melanoma patients (human and animals) and describe some of the challenges that will need to be addressed before EVs can be introduced in the clinical setting.

https://www.mdpi.com/1424-8247/13/12/475/pdf

Circulating Melanoma-Derived Extracellular Vesicles: Impact on Melanoma Diagnosis, Progression Monitoring, and Treatment Response.

Simple Summary Melanocytic tumors are among the most common cutaneous neoplasms in horses. Contrary to popular opinion, the slow rate of growth typical of these tumors does not warrant benign classification. Furthermore, the wide spectrum of treatment modalities can generate some frustration for equine practitioners. This narrative review aims to give an overview of the genetic basis, linked with melanoma development, of alterations in STX17, ASIP and MITF genes, a description of the clinical and pathological differences between naevus, dermal melanoma, dermal melanomatosis and anaplastic malignant melanoma, as well as a description of the role of the different diagnostic tools, mainly fine needle aspiration, histopathology and immunohistochemistry. The most common treatment modalities, such as surgery, chemotherapy and electroporation are reviewed, and a description of less common options, such as immunotherapy and radiotherapy is presented. The article also elucidates future perspectives and research fields about equine melanocytic tumors, mainly in the search for new therapeutical targets, such as CD47, PD-1 and COX-2. Abstract Adult grey horses have a high incidence of melanocytic tumors. This article narratively reviews the role of some genetic features related to melanoma formation in horses, such as STX17 mutation, ASIP or MITF alterations, and the link between the graying process and the development of these tumors. A clear system of clinical and pathological classification of melanocytic tumors in naevus, dermal melanoma, dermal melanomatosis and anaplastic malignant melanoma is provided. Clinical and laboratorial methods of diagnosing are listed, with fine needle aspiration and histopathology being the most relevant. Relevance is given to immunohistochemistry, describing potentially important diagnostic biomarkers such as RACK1 and PNL2. Different therapeutical options available for equine practitioners are mentioned, with surgery, chemotherapy and electroporation being the most common. This article also elucidatesnew fields of research, perspectives, and new therapeutic targets, such as CD47, PD-1 and COX-2 biomarkers.

/pdf/equine-melanocytic-tumors-a-narrative-review-3b1fjizu.pdf

Equine Melanocytic Tumors: A Narrative Review

In horses, penile squamous cell carcinomas (epSCCs) are among the most common cutaneous neoplastic lesions. These tumors usually arise in benign lesions such as viral plaques and papillomas frequently induced by Equus caballus papillomavirus type 2 (EcPV2) infection. In the last decade, the introduction of immune checkpoint inhibitors (ICI) for the treatment of human cancers has demonstrated promising results. Among the most commonly targeted pathways, there is PD-1/PD-L1 and CTLA-4. The aim of this study is to investigate the expression of the PD-1/PD-L1 pathway and CTLA-4 in the tumor microenvironment of epSCCs to assess the feasibility of an immunotherapeutic approach. Twenty equine epithelial tumors were retrospectively selected and submitted to RT-qPCR for PD-1 and PD-L1 genes. After testing antibodies cross-reactivity by western blotting, immunohistochemistry for PD-L1 and CTLA-4 was performed. Results from RT-qPCR demonstrated that 3/20 cases expressed the PD-L1 gene, whereas the PD-1 gene was not detected. Immunohistochemical positivity for PD-L1 was found only in one case. CTLA-4-positive cells were observe in all cases but were few (Mdn = 4.8; IQR = 2.3-7.1 cells/HPF). In this study group, PD-1/PD-L1 and CTLA-4 do not appear to be highly expressed and therefore the use of ICI in epSCCs may not have promising rates of response.

https://www.mdpi.com/2076-2615/11/7/2121/pdf

PD-L1/PD-1 and CTLA-4 expression in equine penile squamous cell carcinomas

Interventions for treatment of cutaneous melanoma in horses: a structured literature review

Currently available treatments for equine melanocytic tumors have limitations, mainly due to mass localization and dimension, or the presence of metastases. Therefore, a search for new therapies is necessary. Programmed cell death-ligand 1 (PD-L1) is expressed by several tumors, blocking T cell-mediated elimination of the tumor cells by binding to programmed cell death protein 1 (PD-1). A novel therapeutic approach using PD-1/PD-L1 blockade in human melanoma resulted in tumor regression and prolonged tumor-free survival. This study aimed to evaluate the immunohistochemical expression of PD-L1 in equine melanocytic tumors. A total of 77 melanocytic tumors were classified as benign or malignant and evaluated by extension of labeling. A total of 59.7% of the tumors showed >50% of immunolabeled cells. Regarding malignant tumors, 24/38 tumors presented >50% of labeled cells, 13 tumors presented between 25–50% and one tumor presented <10%. Regarding benign tumors, 22/39 tumors presented >50% of labeled cells, nine tumors presented 25–50%, three tumors presented 10–25%, two tumors presented <10% and three tumors did not present expression. Our results suggest that PD-L1 blockade may be a potential target for immunotherapy in equine melanocytic tumors and that future clinical research trials into the clinical efficacy of the anti-PD-L1 antibody are necessary.

Programmed Cell Death-Ligand 1 (PD-L1) Immunohistochemical Expression in Equine Melanocytic Tumors

Programmed death-1 (PD-1) is an immunoinhibitory receptor expressed on exhausted T cells during chronic illness. Interaction of PD-1 with its ligand PD-ligand 1 (PD-L1) delivers inhibitory signals and impairs proliferation, cytokine production, and cytotoxicity of T cells. We reported that the PD-1/PD-L1 pathway is closely associated with T-cell exhaustion and disease progression in bovine chronic infections and canine tumors. Moreover, we found that blocking antibodies targeting PD-1 and PD-L1 restore T-cell functions and may be used in immunotherapy in cattle and dogs. However, the immunological role of the PD-1/PD-L1 pathway remains unclear for chronic equine diseases, including tumors. In this study, we identified nucleotide sequences of equine PD-1 (EqPD-1) and PD-L1 (EqPD-L1) and investigated the role of anti-bovine PD-L1 monoclonal antibodies (mAbs) against EqPD-L1 using  in vitro  assays. We also evaluated the expression of PD-L1 in tumor tissues of equine malignant melanoma (EMM).

The amino acid sequences of EqPD-1 and EqPD-L1 share a high identity and similarity with homologs from other mammalian species. Two clones of the anti-bovine PD-L1 mAbs recognized EqPD-L1 in flow cytometry, and one of these cross-reactive mAbs blocked the binding of equine PD-1/PD-L1. Importantly, PD-L1 expression was confirmed in EMM tumor tissues by immunohistochemistry. A cultivation assay revealed that PD-L1 blockade enhanced the production of Th1 cytokines in equine immune cells. 

These results suggest that our anti-PD-L1 mAbs may be useful for investigating the expression and role of the equine PD-1/PD-L1 pathway. Further research is required to discover the immunological role of PD-1/PD-L1 in chronic equine diseases and elucidate a future application in immunotherapy for horse.

/pdf/pd-l1-expression-in-equine-malignant-melanoma-and-functional-10nlh3o6fb.pdf

PD-L1 expression in equine malignant melanoma and functional effects of PD-L1 blockade

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PD-L1 expression in equine malignant melanoma and functional effects of PD-L1 blockade