Class Switching is Required for Antigen-Dependent B Cell Anti-Tumor Activity

Abstract Recent clinical studies demonstrated a positive correlation between B cell parameters and response to immune checkpoint blockade therapy. However, the potential mechanisms underlying B cell anti-tumor activities are still unclear. A better understanding of B cell-mediated immune responses in cancer will highlight novel vantage points to exploit therapeutically. To this end, we engineered tumor cells to express the B cell model antigen hen egg lysozyme (HEL). Adoptive transfer of CD45.1+ HEL-specific B cells (SWHEL B cells) into wild-type mice bearing HEL+ tumors significantly delayed tumor growth. SWHEL B cells from tumor-draining lymph nodes showed higher levels of MHCII expression, germinal center (GC) formation and class switch rate than non-tumor specific B cells. Of note, MD4 B cells, which recognize HEL but cannot class switch, were unable to control tumor growth, suggesting that immunoglobulin class M are not required for B cell anti-tumor activities. Accordingly, depletion of CD4 T cells (which are required for class switch) in mice bearing HEL+ tumors reverted the anti-tumor activity of SWHEL B cells. GC SWHEL B cells class switched to immunoglobulin G1 with a frequency between 20 and 80%, and resulted in a 10-fold increase of plasmablast (CD19+CD138+) and memory B cell (CD19+IgD-CD38+CCR6+) generation, as compared to non-tumor specific B cells. Collectively, these data point to a role for class-switched B cells and CD4 T cells in tumor immunosurveillance. Future studies will assess the ability of tumor antigen-specific B cells in priming naïve CD4 T cells and the role of other immunoglobulin classes in tumor control and escape. Supported by V Foundation for Cancer Research V2019-012