03261-A: Mechanisms of Immunotolerance in Canine Oral Melanoma: An Opportunity for Comparative Approaches

Naturally occurring canine oral melanoma has been proposed as a model to gain insights into human mucosal melanoma. The species share multiple similarities such as occurrence, course of disease, treatment response, and more importantly, high malignancy and refractoriness to conventional treatment. One critical mechanism associated with poor prognosis is suppression of the immune system by the cancer cells, leading to uncontrolled tumor growth, tumor progression, and metastasis.During the last decade, it has been demonstrated that melanoma cells can overexpress a protein known as PD-L1, which blocks the effect of T cells after binding with the programmed cell death receptor-1 (PD-1) on these exhausted immune cells. This interaction induces an immunosuppressive tumor microenvironment, promoting tumor growth and metastasis.

Although immunotherapies in humans that block the interaction between PD-1 and its ligand PD-L1 have shown promise, some patients with treatment resistance have shown increased expression of PD-L2, an alternative ligand for PD-1. As in humans, overexpression of the PD-axis, including PD-L2, has been reported in canine melanoma and a better understanding of the tumor immunologic microenvironment is necessary to understand their role in metastasis and treatment resistance. In humans, the TANK-binding kinase 1 (Tbk1) protein can directly activate PD-L1, and has been proposed as a potential target for combined therapies.

The goal of this project is to characterize melanomas based on their ability to modulate the immune system and develop metastasis. The researchers anticipate their findings will provide novel insights on the tumor microenvironment and mechanisms of metastasis using a comparative approach.