Abstract
Investigation of canine T cell immunophenotypes in canine melanomas as prognostic biomarkers for disease progression or predictive biomarkers for targeted immunotherapeutics remains in preliminary stages. We aimed to examine T cell phenotypes and function in peripheral blood mononuclear cells (PBMC) and baseline tumor samples by flow cytometry, and to compare patient (n = 11–20) T cell phenotypes with healthy controls dogs (n = 10–20). CD3, CD4, CD8, CD25, FoxP3, Ki67, granzyme B, and interferon-γ (IFN-γ) were used to classify T cell subsets in resting and mitogen stimulated PBMCs. In a separate patient cohort (n = 11), T cells were classified using CD3, CD4, CD8, FoxP3, and granzyme B in paired PBMC and single cell suspensions of tumor samples. Analysis of flow cytometric data of individual T cell phenotypes in PBMC revealed specific T cell phenotypes including FoxP3+ and CD25+FoxP3- populations that distinguished patients from healthy controls. Frequencies of IFN-γ+ cells after ConA stimulation identified two different patient phenotypic responses, including a normal/exaggerated IFN-γ response and a lower response suggesting dysfunction. Principle component analysis of selected T cell immunophenotypes also distinguished patients and controls for T cell phenotype and revealed a clustering of patients based on metastasis detected at diagnosis. Findings supported the overall hypothesis that canine melanoma patients display a T cell immunophenotype profile that is unique from healthy pet dogs and will guide future studies designed with larger patient cohorts necessary to further characterize prognostic T cell immunophenotypes.
Highlights
Immunotherapy has shown great promise in the treatment of melanoma in humans, including those with an advanced stage of disease, but a majority of patients still fail to respond long term to these therapies and a high rate of toxicity is associated with their use [1,2,3,4]
Tcell immunophenotyping studies described were predicated on the hypothesis that canine melanoma patients exhibit a T cell immune profile that is different from healthy control pet dogs
Findings by principal component analysis (PCA) determined that canine melanoma patients display a T cell immunophenotype that is unique from healthy pet dogs
Summary
Immunotherapy has shown great promise in the treatment of melanoma in humans, including those with an advanced stage of disease, but a majority of patients still fail to respond long term to these therapies and a high rate of toxicity is associated with their use [1,2,3,4]. Oral melanoma is the most commonly occurring malignant tumor in the oral cavity of dogs [11]. The majority of these canine tumors are malignant in nature with a high metastatic rate, a more benign variant has been reported [12]. Radiotherapy and clinical trials with traditional cancer vaccines [13,14,15,16], the majority of dogs with oral melanoma die of their disease as was the case in human medicine prior to the advent of more targeted immunotherapies, most patients in human medicine still are not cured despite these advances [4, 17]
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