Understanding the cross-talk among regulatory immune cells in lymphomas: A link to improve the efficacy of immunotherapeutic strategies

Recent data in animal models suggest that regulatory B cells (B regs ) may promote cancer metastasis and limit the therapeutic efficacy of B-cell depletion therapies (BDT) with monoclonal antibodies (mAb). On one hand, B regs cells support metastatic growth by converting CD4 T cells to regulatory T cells (T regs ) that promote escape from host protective immune cells. On the other hand, B regs cells negatively regulate innate immune cells and reduce surface ex pression of Fcgreceptor on monocytes, thereby inhibiting the therapeutic efficacy of rituximab, a mAb directed against CD20 antigen, commonly used in the treatment of autoimmune diseases and B-cell malignancies such as lymphomas. Interestingly, even small numbers of residual murine B regs cells were able to inhibit rituximab activity and only their total removal was associated with an optimal clearance of malignant B cells. Thus, it becomes clear that a link may exist among B regs cells, T regs cells, cancer escape and rituximab efficacy. The better we understand this link, the more able we would be to improve the efficacy of immunotherapeutic strategies used in lymphomas, which are the second top cause among the most common diagnosed cancers in the Sultanate of Oman, with a frequency of 8.6%. To date, no studies have addressed whether there might be an involvement of human B regs cells in affecting BDT. Therefore, we plan to focus our efforts on a comprehensive understanding of human B regs cell subsets in lymphoma patients who received rituximab as part of their standard therapy. Specifically, we will prospectively investigate changes in circulating B regs cells using well-established methods such as immunophenotyping, cell sorting, mixed cell culture and RT-PCR techniques. We will also determine the potential clinical value of measurement of B regs cell subsets and their capacity to generate and expand T regs cells. Additionally, we will evaluate whether the observed frequencies and absolute counts of B regs cell subsets correlate with clinical outcomes of lymphoma patients. We anticipate that this study will shed new light on the role of human B regs cells in influencing BDT. Consequently, further identification, characterization and enumeration of B regs cell subsets and their link with T regs cells may help explain some of the features and outcomes of lymphoma patients treated with rituximab. Such information will also serve to identify the molecular mechanisms that govern the imbalances in positive and negative regulation of B regs cells, and changes in their phenotypic distribution during BDT. Furthermore, this study will open new avenues to improve immunotherapeutic strategies in lymphomas and other clinical conditions using mAb against B cell antigens.