B Cells: At the intersection of enhanced responses to immunotherapy treatments
B cells have strong clinical significance as drivers of antitumor immunity in triple negative breast cancer. While B cells are known to enhance T cell-mediated tumor killing, we have also uncovered a potential regulatory function, in which they suppress myeloid-derived suppressor cells.
Immune checkpoint blockade (ICB) has surged to the forefront of cancer therapy with durable responses in many forms of cancer. However, the percentage of patients that respond to ICB is low and solid tumor phenotypes often exhibit a highly suppressive microenvironment that is not conducive to successful treatment with ICB as a monotherapy. For this reason, many clinical trials and preclinical studies aim to combine ICB with other therapeutic modalities to enhance antitumor immunity and prolong durable responses to therapy.
In our work, we have combined a clinical chemotherapy regimen (FEC; 5-fluorouracil, epirubicin, cyclophosphamide) with oncolytic virotherapy (oHSV-1; oncolytic herpes simplex virus type 1) and shown that this platform allows otherwise non-responsive murine tumors to respond to ICB therapy. As we investigated this phenomenon and the underlying biological and immunological drivers of therapeutic efficacy, we uncovered a strong B cell signature that was promoted in mice treated with our FEC + oHSV-1 therapy. Further to this, when we depleted circulating B cells one day prior to the start of treatment, we saw a complete loss of therapeutic efficacy. This dependence on the presence of B cells for durable responses to therapy (when treated with ICB) is in line with literature findings across other cancer types, where researchers have shown tumor-infiltrating B cells as being necessary for maintaining the required inflammation needed for successful treatment with ICB.
We followed up this B-cell-dependency and investigated changes to other immune cell populations in the absence of B cells. While most immune cell types were unchanged with or without B cells present, myeloid-derived suppressor cells (MDSCs) were controlled in mice with B cells present, but rapidly expanded in mice that were depleted of B cells. While many studies in the literature have shown the ability of MDSCs to inhibit B cell functionality in a direct cell-to-cell contact interaction, our data suggests that the inverse relationship may also be true, with B cells able to impair MDSC immunosuppression in the tumor microenvironment (TME).
Though we did not show the exact mechanism by which this regulation occurs, we believe that B cells switch the cytokine expression profile in the TME, forcing these otherwise immature myeloid cells to fully differentiate to other cells of the myeloid lineage, decreasing the accumulation of MDSCs in the TME. To follow up on this dynamic interaction at the immunological synapse between B cells and MDSCs, we aim to further characterize the mechanism of regulation and also assess whether or not there is inhibition through direct cell-to-cell contact as well. These findings are impactful to the broader cancer community as we try to better understand the underlying biology associated with novel immunotherapy treatments coming down the clinical pipeline.