A Review of Immunotherapeutic Strategies in Canine Malignant Melanoma

Despite promising immunotherapy strategies in human melanoma, there are few studies on the immune environment of canine melanocytic tumors. In humans, the activation of immunosuppressive cell subpopulations, such as regulatory T cells (Tregs) that express forkhead box protein P3 (FoxP3), the engagement of immunosuppressive surface receptors like cytotoxic T lymphocyte antigen (CTLA-4), and the secretion of molecules inhibiting lymphocyte activation, such as indoleamine-pyrrole 2,3-dioxygenase (IDO), are recognized as immunoescape mechanisms that allow tumor growth and progression. The aim of our study was to investigate the expression of these immunosuppression markers in canine melanocytic tumors and to postulate their possible role in melanoma biology and progression. Fifty-five formalin-fixed, paraffin-embedded canine melanocytic tumors (25 oral melanomas; 20 cutaneous melanomas; 10 cutaneous melanocytomas) were selected to investigate the expression of FoxP3, CTLA-4, and IDO by immunohistochemistry and RT-qPCR (real-time quantitative polymerase chain reaction). All of the tested markers showed high gene and protein expression in oral melanomas and were differently expressed in cutaneous melanomas when compared to their benign counterpart. IDO expression was associated with an increased hazard of death both in univariable and multivariable analyses ( P < .05). FoxP3 protein expression >6.9 cells/HPF (high-power field) was an independent predictor of death ( P < .05). CTLA-4 gene and protein expressions were associated with a worse prognosis, but only in the univariable analysis ( P < .05). FoxP3, CTLA-4, and IDO likely play a role in canine melanoma immunoescape. Their expression, if supported by future studies, could represent a prognostic tool in canine melanoma and pave the way to future immunotherapeutic approaches in dogs.

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“…54 In veterinary medicine, there are fewer studies on cancer immunity and on the application of immunotherapy. 2,39,58,60…”

Section: Discussionmentioning

confidence: 99%

FoxP3, CTLA-4, and IDO in Canine Melanocytic Tumors

et al. 2020

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“…Immunotherapy is a novel treatment modality which consists of treating cancers using and stimulating the patient’s immune system. It has revolutionized some advanced cancer’s treatment and outcome, particularly with the development of checkpoint inhibitors targeting cytotoxic T lymphocytes antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) [122,123]. Those molecules are mainly expressed on activated T lymphocytes, and the binding to their ligands (several clusters of differentiation for CTLA-4 and programmed cell death ligands 1 and 2 for PD-1) suppresses T-cell activity.…”

Section: Innovative Therapies In Human and Canine Melanomasmentioning

confidence: 99%

Canine Melanomas as Models for Human Melanomas: Clinical, Histological, and Genetic Comparison

Prouteau

André

2019

Genes

109

110

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Despite recent genetic advances and numerous ongoing therapeutic trials, malignant melanoma remains fatal, and prognostic factors as well as more efficient treatments are needed. The development of such research strongly depends on the availability of appropriate models recapitulating all the features of human melanoma. The concept of comparative oncology, with the use of spontaneous canine models has recently acquired a unique value as a translational model. Canine malignant melanomas are naturally occurring cancers presenting striking homologies with human melanomas. As for many other cancers, dogs present surprising breed predispositions and higher frequency of certain subtypes per breed. Oral melanomas, which are much more frequent and highly severe in dogs and cutaneous melanomas with severe digital forms or uveal subtypes are subtypes presenting relevant homologies with their human counterparts, thus constituting close models for these human melanoma subtypes. This review addresses how canine and human melanoma subtypes compare based on their epidemiological, clinical, histological, and genetic characteristics, and how comparative oncology approaches can provide insights into rare and poorly characterized melanoma subtypes in humans that are frequent and breed-specific in dogs. We propose canine malignant melanomas as models for rare non-UV-induced human melanomas, especially mucosal melanomas. Naturally affected dogs offer the opportunity to decipher the genetics at both germline and somatic levels and to explore therapeutic options, with the dog entering preclinical trials as human patients, benefiting both dogs and humans.

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“…Therefore, this review will summarize key aspects of the dog cancer model that make it particularly well-suited to evaluating cancer immunotherapies and drug combinations. This will not however be a comprehensive review of all dog cancer immunotherapy studies, which have been reviewed elsewhere and are beyond the scope of this work (3,(14)(15)(16)(17)(18)(19)(20). We will instead focus on areas of investigation in which the dog model currently may be most likely to impact clinical immuno-oncology research and new drug development.…”

Section: Introductionmentioning

confidence: 99%

A Role for Dogs in Advancing Cancer Immunotherapy Research

Dow

2020

Front. Immunol.

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While rodent cancer models are essential for early proof-of-concept and mechanistic studies for immune therapies, these models have limitations with regards to predicting the ultimate effectiveness of new immunotherapies in humans. As a unique spontaneous, large animal model of cancer, the value of conducting studies in pet dogs with cancer has been increasingly recognized by the research community. This review will therefore summarize key aspects of the dog cancer immunotherapy model and the role that these studies may play in the overall immunotherapy drug research effort. We will focus on cancer types and settings in which the dog model is most likely to impact clinical immuno-oncology research and drug development. Immunological reagent availability is discussed, along with some unique opportunities and challenges associated with the dog immunotherapy model. Overall it is hoped that this review will increase awareness of the dog cancer immunotherapy model and stimulate additional collaborative studies to benefit both man and man's best friend.

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A Review of Immunotherapeutic Strategies in Canine Malignant Melanoma

Cited by 26 publications

References 59 publications

FoxP3, CTLA-4, and IDO in Canine Melanocytic Tumors

FoxP3, CTLA-4, and IDO in Canine Melanocytic Tumors

Canine Melanomas as Models for Human Melanomas: Clinical, Histological, and Genetic Comparison

A Role for Dogs in Advancing Cancer Immunotherapy Research

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