Cancer immunology and canine malignant melanoma: A comparative review

Abstract

Canine melanoma as a model of human melanomaFor at least two decades, veterinary oncologists have advocated using spontaneously occurring tumours in companion animals as models for human cancer (Knapp and Waters, 1997;MacEwen, 1990). Several recent reviews have readdressed this approach identifying osteosarcoma, mammary tumours, head and neck cancers, bladder carcinomas, non-Hodgkin lymphoma, prostatic carcinoma, lung cancer and pertinently oral canine malignant melanoma (CMM) as good models for human neoplasms (Hansen and Khanna, 2004;Khanna and Hunter, 2005;Paoloni and Khanna, 2008). The major benefits of dogs as tumour models include the ability to study genetically outbred and immunologically intact animals in which cancers develop spontaneously and thus, more likely reflect the process of tumourigenesis compared to experimentally-induced neoplasms. As pets and owners share the same environment, they may be exposed to the same carcinogens, which, in part, drive tumour development. Regarding disease modelling, animal tumours often have similar clinical presentation, tumour biology and histopathological appearance to their human counterparts and usually progress more rapidly, thereby shortening data maturation times. In addition, few "standard of care" therapies exist for dogs meaning that within reason, trial therapeutics can be instigated at any point. Given these benefits, companion animal tumour models more accurately reflect the features of human cancers compared to rodent models with CMM being a desirable example of one such neoplasm. Conversely, the opportunity to translate the potential value of state of the art human therapeutics to the veterinary clinic also exists. Oral canine malignant melanoma (CMM) is a spontaneously occurring aggressive tumour with relatively few medical treatment options, which provides a suitable model for the disease in humans. Historically, multiple immunotherapeutic strategies aimed at provoking both innate and adaptive anti-tumour immune responses have been published with varying levels of activity against CMM. Recently, a plasmid DNA vaccine expressing human tyrosinase has been licensed for the adjunct treatment of oral CMM. This article reviews the immunological similarities between CMM and the human counterpart; mechanisms by which tumours evade the immune system; reasons why melanoma is an attractive target for immunotherapy; the premise of whole cell, dendritic cell (DC), viral and DNA vaccination strategies alongside preliminary clinical results in dogs. Current "gold standard" treatments for advanced human malignant melanoma are evolving quickly with remarkable results being achieved following the introduction of immune checkpoint blockade and adoptively transferred cell therapies. The rapidly expanding field of cancer immunology and immunotherapeutics means that rational targeting of this disease in both species should enhance treatment outcomes in veterinary and human clinics.

Canine oral primary melanoma cells exhibit shift to mesenchymal phenotype and phagocytic behaviour

“…A primary tumour and a metastasis (1.2) tissue section, as well as all primary cell lines were assessed for expression of the melanoma markers Melan A (Mart‐1), PNL2, and CD146, as well as macrophage marker CD68 using IHC or IF for tissue, and flow cytometry for cell analysis, with canine melanoma cell lines Shadow, or DH82 (for CD68) serving as positive controls. As negative control, specific antibodies were omitted (IHC/IF) or substituted by corresponding IgG isotype antibodies in the different assays.…”

“…All lesions underwent histopathological examination, leading to the diagnosis of COMM in all cases. Tumour material consisted of a fine needle aspiration biopsy (FNAB) from a primary predominantly amelanotic palatal COMM and biopsies from metastases affecting the right (1.1; Ø 4 cm) and the left mandibular lymph node (1.2; Ø 2 cm) of a castrated female 11‐year‐old mongrel; a biopsy from a low pigmented mandibular COMM diagnosed in a castrated male 15‐year‐old mongrel; a biopsy from an amelanotic mandibular COMM detected in a female spayed 11‐year‐old Papillon; and a biopsy from a pigmented COMM affecting the right oral commissure of a male 9‐year‐old Golden Retriever.…”

“…A primary tumour 3 Figure S1). Importantly, both tumour sections analysed stained clearly positive for CD146 ( Figure 2A).…”

“…In general, canine and human MM display striking similarities at clinical, histopathological and molecular level . For example, canine and human MMs typically show activation of the activated protein kinase B mechanistic Target of Rapamycin pathway, tyrosine Kinase kit aberrations, cyclooxygenase‐2 and chondroitin sulfate proteogycan 4 overexpression and deregulation of the Wnt/β‐catenin pathway . A high degree of resemblance on cellular and subcellular level is particularly observed between canine oral MM (COMM) and human mucosal MM .…”

Kombinierte Anwendung von Strahlentherapie und adjuvanter Therapie mit einem Mistelextrakt (<b><i>Viscum album </i></b>L.) zur Behandlung des oralen malignen Melanoms beim Hund: Eine retrospektive Studie

“…Die aktuell verfügbare wissenschaftliche Literatur lässt weder die Chemotherapie noch die Vakzine [4,25] als über jeden Zweifel erhabene adjuvante Therapie zur Strahlentherapie des caninen oralen Melanoms erscheinen.…”