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.

中文翻译：

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犬多中心淋巴瘤表现出全身性和肿瘤内细胞因子失调。

非霍奇金淋巴瘤（NHL）是犬和人类中最常见的肿瘤。由于其与人类对应物的显着相似性，犬淋巴瘤（cNHL）模型已被提议作为一种强大的框架，可以快速而临床相关地翻译新型免疫疗法。但是，cNHL作为临床前预测模型的建立已受到犬免疫系统有限特征的阻碍。细胞因子是肿瘤与其微环境之间相互作用的关键因素。在人类NHL中，多种细胞因子与淋巴瘤的发生有关，并且是治疗反应和预后的相关生物标志物。相反，很少有研究研究cNHL中的细胞因子。在此背景下，本研究旨在研究cNHL中的细胞因子调控。成功建立了多中心cNHL生物库。通过qRT-PCR分析肿瘤组织和循环PBMC中的细胞因子mRNA谱，并与健康对照组进行比较。使用特异性引物评估Th1，Th2和Th17反应。使用包括IL-2，IL6，IL-10和TNF-α的市售犬多重测定法测量全身细胞因子浓度，并与健康对照组进行比较。我们的结果证明了细胞因子mRNA表达失调，代表了cNHL中的肿瘤微环境和全身反应。瘤内细胞因子反应显示体液和Th1反应明显下调。全身反应显示出独特的mRNA模式，但是免疫抑制也占主导。细胞因子血清定量显示cNHL中IL-10浓度显着增加。描述了血液学参数的显着差异，并显示了IL-6蛋白血清水平与中性粒细胞计数之间的相关性。最后，数据分析表明，基线治疗前IFN-γ组织mRNA的水平与生存结果相关，预示对化疗的良好反应。总而言之，这些结果表明cNHL在细胞因子应答中表现出局部和全身性失调。通过确认并扩展先前的研究，我们的工作有助于评估潜在的细胞因子候选物用于诊断，预后和治疗干预，因此为比较肿瘤学增添了价值。描述了血液学参数的显着差异，并显示了IL-6蛋白血清水平与中性粒细胞计数之间的相关性。最后，数据分析表明，基线治疗前IFN-γ组织mRNA的水平与生存结果相关，预示对化疗的良好反应。总而言之，这些结果表明cNHL在细胞因子应答中表现出局部和全身性失调。通过确认和扩展先前的研究，我们的工作为评估潜在的细胞因子候选物以进行诊断，预后和治疗干预做出了贡献，因此为比较肿瘤学增加了价值。描述了血液学参数的显着差异，并显示了IL-6蛋白血清水平与中性粒细胞计数之间的相关性。最后，数据分析表明，基线治疗前IFN-γ组织mRNA的水平与生存结果相关，预示对化疗的良好反应。总而言之，这些结果表明cNHL在细胞因子应答中表现出局部和全身性失调。通过确认并扩展先前的研究，我们的工作有助于评估潜在的细胞因子候选物用于诊断，预后和治疗干预，因此为比较肿瘤学增添了价值。预测对化疗的有利反应。总而言之，这些结果表明cNHL在细胞因子应答中表现出局部和全身性失调。通过确认和扩展先前的研究，我们的工作为评估潜在的细胞因子候选物以进行诊断，预后和治疗干预做出了贡献，因此为比较肿瘤学增加了价值。预测对化疗的有利反应。总而言之，这些结果表明cNHL在细胞因子应答中表现出局部和全身性失调。通过确认和扩展先前的研究，我们的工作为评估潜在的细胞因子候选物以进行诊断，预后和治疗干预做出了贡献，因此为比较肿瘤学增加了价值。