Canine melanoma: A review of diagnostics and comparative mechanisms of disease and immunotolerance in the era of the immunotherapies

Abstract

Melanomas in humans and dogs are highly malignant and resistant to therapy. Since the first development of immunotherapies, interest in how the immune system interacts within the tumor microenvironment and plays a role in tumor development, progression, or remission has increased. Of major importance are tumor-infiltrating lymphocytes (TILs) where distribution and cell frequencies correlate with survival and therapeutic outcomes. Additionally, efforts have been made to identify subsets of TILs populations that can contribute to a tumor-promoting or tumor-inhibiting environment, such as the case with T regulatory cells versus CD8 T cells. Furthermore, cancerous cells have the capacity to express certain inhibitory checkpoint molecules, including CTLA-4, PD-L1, PD-L2, that can suppress the immune system, a property associated with poor prognosis, a high rate of recurrence, and metastasis. Comparative oncology brings insights to comprehend the mechanisms of tumorigenesis and immunotolerance in humans and dogs, contributing to the development of new therapeutic agents that can modulate the immune response against the tumor. Therapies that target signaling pathways such as mTOR and MEK/ERK that are upregulated in cancer, or immunotherapies with different approaches such as CAR-T cells engineered for specific tumor-associated antigens, DNA vaccines using human tyrosinase or CGSP-4 antigen, anti-PD-1 or -PD-L1 monoclonal antibodies that intercept their binding inhibiting the suppression of the T cells, and lymphokine-activated killer cells are already in development for treating canine tumors. This review provides concise and recent information about diagnosis, comparative mechanisms of tumor development and progression, and the current status of immunotherapies directed toward canine melanoma.

PD-1, PD-L1, and PD-L2 Gene Expression and Tumor Infiltrating Lymphocytes in Canine Melanoma

“…5,30 Similarly, canine melanoma is also very aggressive, with median survival time of 22 months after diagnosis for cutaneous melanoma, 5 months for oral melanoma, and <3 months for stage 3 (metastatic) disease. 25 However, in contrast with humans where point mutations in the BRAF family are associated with 50% of the cases, this mutation appears to be rare in canine melanoma 24,38 (Stevenson, Huckle, LeRoith, unpublished data), and few convincing driver mutations have been described for canine melanomas. 10,13,34 Because of this, the dog has been proposed as an attractive animal model to study the oncogenic mechanisms in human triple wild-type (lacking any of the known driver mutations in BRAF , RAS , or NF1 ) and mucosal melanomas, which comprise almost 40% of the total human melanoma cases.…”

Unveiling the Role of Endoplasmic Reticulum Stress Pathways in Canine Demodicosis

“…These pathways have also been shown to be inextricably linked [16,49] and all have been shown to be involved in the modulation of TLRs [50,51]. Moreover, these pathways have been previously demonstrated to play a role in the pathogenesis of skin diseases such as rosacea, psoriasis, atopic dermatitis and melanoma in both dogs and humans [52][53][54][55][56]. Cell stress, whether from internal or external sources, can cause improper protein folding, resulting in the accumulation of misfolded or unfolded proteins in the endoplasmic reticulum (ER), known as ER stress.…”

“…These pathways have also been shown to be inextricably linked [16, 49] and all have been shown to be involved in the modulation of TLRs [50, 51]. Moreover, these pathways have been previously demonstrated to play a role in the pathogenesis of skin diseases such as rosacea, psoriasis, atopic dermatitis and melanoma in both dogs and humans [52–56].…”

Atypical magnetic resonance imaging findings of a vertebral melanotic melanoma in a dog

“…Melanoma is one of the most aggressive and metastatic neoplasms in both humans and dogs. 1 Melanocytic neoplasms are relatively common in dogs, accounting for 3% of all neoplasms and 7% of all malignant tumours. 2 Studies are controversial about the most frequently affected sites; however, most point to the oral cavity, skin and digits, with other sites, including the eye, accounting for only 2%.…”

“…Melanoma is one of the most aggressive and metastatic neoplasms in both humans and dogs 1 . Melanocytic neoplasms are relatively common in dogs, accounting for 3% of all neoplasms and 7% of all malignant tumours 2 .…”