Examining the Role of Regulatory Lymphocytes in a Mouse Model of BCL1 Tumor Dormancy

Cancer dormancy is a clinical state where residual tumor cells persist for long periods but do not cause detectable disease. However, tumor regrowth can occur and is accompanied by resistance to treatment and high mortality rates. The mechanisms that mediate tumor dormancy have been studied using the mouse B cell lymphoma (BCL1) model of tumor dormancy. However, the events that lead to cancer relapse are not known since the tumor microenvironment consists of many cell types that either facilitate or prevent tumor progression or have a dual role depending on the disease stage. Regulatory T (Treg) cells play a key role in maintaining systemic immune tolerance and have been described to promote cancer progression. The objective of this study was to determine the role of Treg cells in preventing BCL1 tumor dormancy by suppressing the anti-tumor immune responses. Surprisingly, we found that the total numbers of Treg cell were highest in mice bearing dormant tumor cells, whereas mice with the highest BCL1 tumor burden had the lowest number of Treg cells in their tumor microenvironment. Moreover, we compared the functional differences between Treg cells isolated from mice bearing dormant tumors and those bearing non-dormant tumors. We found that they equally suppressed T cell subsets from their respective tumor microenvironments. Treg cells have also been shown to suppress B cells. Since the BCL1 tumor cells are malignant B cells, we examined the effects of Treg cells on the tumor cells themselves. We found that Treg cells did not suppress the proliferation nor inhibit IgM secretion by the tumor cells. Interestingly, we then found that the BCL1 tumor cells shared features with regulatory B (Breg) cells. Like Treg cells, Breg cells also induce immune tolerance by suppressing effector T cells. The BCL1 tumor cells homogeneously expressed the characteristic phenotype (CD1dhiCD5+) and cytokine profile (secretion of high levels of IL-10) of the B10 subset of Breg cells. Moreover, the tumor cells directly induced T cell apoptosis through a cell-contact dependent, caspase-3-mediated pathway. Therefore, the adoption of Breg cell characteristics may be another approach that BCL1 tumor cells employ to evade immune responses. [Keywords: B cell lymphoma, tumor dormancy, regulatory T cells, regulatory B cells, suppression assays, immunization, flow cytometry, cytokine profile]