Abstract
The cancer microenvironment plays a pivotal role in oncogenesis, containing a number of regulatory cells that attenuate the anti-neoplastic immune response. While the negative prognostic impact of regulatory T cells (Tregs) in the context of most solid tissue tumors is well established, their role in lymphoid malignancies remains unclear. T cells expressing FOXP3 and Helios were documented in the fine needle aspirates of affected lymph nodes of dogs with spontaneous multicentric B cell lymphoma (BCL), proposed to be a model for human non-Hodgkin lymphoma. Multivariable analysis revealed that the frequency of lymph node FOXP3+ T cells was an independent negative prognostic factor, impacting both progression-free survival (hazard ratio 1.10; p = 0.01) and overall survival (hazard ratio 1.61; p = 0.01) when comparing dogs showing higher than the median FOXP3 expression with those showing the median value of FOXP3 expression or less. Taken together, these data suggest the existence of a population of Tregs operational in canine multicentric BCL that resembles thymic Tregs, which we speculate are co-opted by the tumor from the periphery. We suggest that canine multicentric BCL represents a robust large animal model of human diffuse large BCL, showing clinical, cytological and immunophenotypic similarities with the disease in man, allowing comparative studies of immunoregulatory mechanisms.
Highlights
Non-Hodgkin lymphoma (NHL), a heterogeneous group of lymphoid malignancies [1,2], is the eleventh most common cause of death from cancer in humans worldwide, estimated to be responsible for approximately 192,000 deaths in 2008 alone [3]
A total of 22 B cell lymphoma (BCL), 14 T cell lymphoma (TCL), 14 reactive hyperplasia (RH), six mast cell tumors (MCTs) and 25 healthy control (HC) dogs were recruited into the study
A summary of the signalment and clinical details of the BCL, TCL, RH, MCT and HC cases is presented in Table 2; further details are presented in Tables S2 to S5
Summary
Non-Hodgkin lymphoma (NHL), a heterogeneous group of lymphoid malignancies [1,2], is the eleventh most common cause of death from cancer in humans worldwide, estimated to be responsible for approximately 192,000 deaths in 2008 alone [3]. There is an urgent need to develop novel, targeted therapies for this group of diseases, driven by advances in our understanding of their pathogenesis and specific prognosis. Key to advancing the field will be the development of natural, polygenic animal models of NHL, allowing the further interrogation of molecular and cellular pathogenesis, as well as trials of novel anti-cancer agents. Its spontaneous development of mesenchymal, epithelial and round cell tumors, relatively short lifespan, and cohabitation of our environment, as well as the availability of advanced diagnostic and therapeutic modalities that are similar to those available in human oncology clinics, all make this species attractive as a model for cancer research [7,9,10]
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