Canine multicentric lymphoma exhibits systemic and intratumoral cytokine dysregulation

Abstract

Non-Hodgkin Lymphoma (NHL) is among the most common neoplasias in dogs and humans. Owing to remarkable similarities with its human counterpart, the canine lymphoma (cNHL) model has been proposed as a powerful framework for rapid and clinically relevant translation of novel immunotherapies. However, the establishment of cNHL as a predictive preclinical model has been hampered by the limited characterization of the canine immune system. Cytokines are key players of the interaction between tumor and its microenvironment. In human NHL, multiple cytokines have been linked to the development of lymphoma and are relevant biomarkers for treatment response and prognosis. In contrast, few studies have investigated cytokines in cNHL. Within this context, this study aimed to investigate cytokine regulation in cNHL. A multicentric cNHL biobank was successfully constructed. Cytokine mRNA profiles in tumor tissue and circulating PBMC were analyzed by qRT-PCR and compared to a healthy control group. Specific primers were used to evaluate Th1, Th2 and Th17 responses. Systemic cytokine concentrations were measured using a commercial canine multiplex assay which included IL-2, IL6, IL-10 and TNF-α, and compared to a healthy control group. Our results demonstrated a dysregulation of cytokine mRNA expression, representative of the tumor microenvironment and systemic response in cNHL. Intratumoral cytokine response revealed a significant downregulation of humoral and Th1 responses. The systemic response demonstrated a distinct mRNA pattern, however immunosuppression also prevailed. Cytokine serum quantification showed a significant increase of IL-10 concentration in cNHL. Significant differences in hematological parameters were described and a correlation between IL-6 protein serum levels and neutrophil count was shown. Finally, data analysis demonstrated that baseline pretreatment IFN-γ tissue mRNA levels were correlated to survival outcome, predicting a favorable response to chemotherapy. Altogether, these results revealed that cNHL presents a local and systemic dysregulation in cytokine response. By confirming and extending previous research, our work contributed for the evaluation of potential cytokine candidates for diagnostic, prognostic purposes and therapeutic intervention, therefore adding value to comparative oncology.

Keywords: Canine lymphoma; Cytokines; Immune dysregulation; Multicentric lymphoma.