Stromal Expression Profiling Reveals Immune-Driven Adaption to Malignancy in Canine Melanoma Subtypes

Area of Science:

• Veterinary oncology
• Cancer biology
• Immunology

Background:

• Canine mucosal melanoma (CMM) is more aggressive than canine cutaneous melanoma (CCM).
• The role of cancer-associated stroma (CAS) in canine melanoma subtypes is not well understood.
• Understanding CAS differences could explain CMM's higher malignancy.

Purpose of the Study:

• To investigate and compare CAS reprogramming in CMM and CCM.
• To correlate CAS changes with prognostic factors and immune cell infiltration.
• To identify potential therapeutic targets by characterizing the CMM stroma.

Main Methods:

• Laser-capture microdissection of CAS from CMM, CCM, and normal tissues.
• RNA sequencing to analyze stromal gene expression.
• Immunohistochemistry and RNA in situ hybridization for immune cell markers (CD3, CD20, CD68) and prognostic factors.

Main Results:

• Stromal reprogramming is evident in both CMM and CCM, but significantly more pronounced in CMM.
• Immune-excluded tumors showed higher mitotic counts (MC) than immune-desert/cold tumors.
• MC correlated with B-cell, T-helper cell, and CTLA4 gene expression in CCM.
• A subset of CMM displayed an immune-suppressive stromal signature with downregulated immune checkpoints.

Conclusions:

• Canine mucosal melanoma exhibits distinct and more significant stromal reprogramming compared to canine cutaneous melanoma.
• Stromal reprogramming in canine melanoma is linked to tumor malignancy and immune cell infiltration.
• The identified immune-suppressive stromal signature in CMM warrants further investigation for therapeutic strategies.