Dissecting the Regulatory Microenvironment of a Large Animal Model of Non-Hodgkin Lymphoma: Evidence of a Negative Prognostic Impact of FOXP3+ T Cells in Canine B Cell Lymphoma

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.

Changes in Foxp3-Positive Regulatory T Cell Number in the Intestine of Dogs With Idiopathic Inflammatory Bowel Disease and Intestinal Lymphoma

“…4,24,25,43 Tumor-infiltrating Tregs have been reported in dogs with osteosarcoma, 5 melanoma, 59 mammary carcinoma, 29,44 seminoma, 28 and multicentric B-cell lymphoma. 39,47 To our knowledge, this is the first study to describe tumor-infiltrating Tregs and their negative prognostic impact in intestinal T-cell lymphoma. Recent studies have also shown that a high Foxp3-positive Treg number is a negative prognostic factor in various types of canine tumors.…”

“…Recent studies have also shown that a high Foxp3-positive Treg number is a negative prognostic factor in various types of canine tumors. 5,29,44,47 Phenotypic and functional analyses have characterized Foxp3-positive Tregs in dogs and demonstrated that they have properties similar to those of human Foxp3-positive Tregs and a potent ability to suppress the proliferation of responder T cells. 31,48 Collectively, these observations suggest that Tregs that migrate into the tumor microenvironment play a significant role in the prognosis of canine cancers, including intestinal small cell lymphoma, by suppressing local antitumor immune responses.…”

Combination Chemotherapy with Firocoxib Induces Reduction of Regulatory T Cells in Dogs with Multicentric B Cell Lymphoma

“…The increase in the number of immunosuppressant Treg cells has been associated with a worse prognosis, as demonstrated in dogs with malignant mammary tumors (Carvalho et al, 2016) and dogs with diffuse large B cell lymphoma, in which an increase in the number of Treg cells was observed in animals with shorter survival time (Pinheiro et al, 2014). In the present study, no difference was observed in the survival time between the treatment groups, suggesting that treatment with firocoxib could promote survival times similar to those of traditional CHOP and, thus, be an alternative option of treatment to patients with lymphoma that have comorbidities that contraindicate the use of prednisone, such as diabetes and hyperadrenocorticism.…”

Companion Animals as Models for Inhibition of STAT3 and STAT5

“…Immune cells pose a significant barrier to the development of cancer, and undergo changes themselves, as cancer cells co-opt the immune response [76,77]. As a result, the tumor influences innate as well as adaptive immune cells to become regulatory, rather than tumoricidal [78,79]. This interplay results in the selection of tumor cells that are invisible to anti-tumor T-cell-mediated destruction, and is central for tumor editing and immune evasion.…”