ALDHhigh cancer stem cells and PD-L1high exosomes suppress anti-tumor effector B cells 2839

Abstract Description We identified antitumor effector B cells which demonstrated significant therapeutic efficacy upon adoptive transfer. We recently found that depletion of B cells prior to anti-PD-L1 administration reduced anti-PD-L1 efficacy and administration of anti-PD-L1recovered the humoral immune response, suggesting the involvement of host B cells in the anti-PD-L1 effect. We detected elevated expression of PD-1 on activated B cells, and higher PD-L1 expression on ALDHhigh cancer stem cells (CSCs). Co-culturing ALDHhigh CSCs with B cells significantly reduced IgG secretion, and such CSC-mediated B cell suppression was rescued by adding anti-PD-L1 mAb in a dose-dependent manner. To investigate if exosomes that express PD-L1 contribute to B cell suppression, we generated Rab27ako D5 cells to delete exosomes. D5-derived exosomes suppressed B cell proliferation and IgG production in vitro, and administration of these exosomes promoted tumor growth and reduced animal survival, revealing the role of tumor-derived exosomes in suppressing B cells. Rab27ako resulted in significantly enhanced host anti-tumor immunity by reducing tumor growth. Furthermore, anti-PD-L1 therapy significantly reduced Rab27ako tumor growth and prolonged animal survival vs. the WT tumor controls. We conclude that PD-L1-expresing CSCs and exosomes suppress antitumor effector B cells; targeting ALDHhigh CSCs and/or Rab27a-relevent exosomal PD-L1 may significantly augment the therapeutic efficacy of anti-tumor B cells. Funding Sources Longenbaugh Foundation Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)