Abstract 1676: Involvement of B cells in the efficacy of anti-PD-L1 antibodies: Suppression of B cells by cancer stem cells
Authors: Leiming Xia, FEI LIAO, Jing Zhang, Ming Lin, Ronald Herbst, Elaine Hurt, Alfred Chang, Max Wicha, Qiao Li
Journal: Cancer Research (2018)

Abstract We reported that adoptive transfer of tumor reactive B cells could mediate tumor regression, and that anti-PD-L1 administration significantly augments the therapeutic efficacy of cancer stem cell (CSC) vaccine. However, whether B cells are involved in the anti-tumor immunity mediated by anti-PD-L1 has not been identified. In the present study, we used two murine models: breast tumor 4T1 and colon cancer CT26. Tumor-bearing mice were administered with anti-CD20 mAb (MB20.11) to deplete B cells prior to anti-PD-L1 mAb administration. Depletion of B cells as compared to the control resulted in more aggressive tumor growth, and the anti-tumor efficacy of anti-PD-L1 was significantly reduced (p=0.041 and p=0.0011 for 4T1 and CT26 respectively), indicating the involvement of host B cells in the function of anti-PD-L1. Mechanistically, the administration of anti-PD-L1 partially recovered the humoral immune response, suggesting that the blockage of PD-L1/PD1 pathway could contribute to the rescue of B cell immune function. We detected higher PD-L1 expression on ALDHhigh CSCs than on ALDHlow non-CSCs or on unsorted tumor cells. On the other hand, we detected elevated expression of PD-1 on activated B cells. While the suppressive effect of CSCs on T cells has well been recognized, the interactions between CSCs and B cells is unknown. We hypothesize that CSCs may suppress B cells either directly via the PD-L1/PD1 immune check point interaction or indirectly via CSC suppression on Th cells. To test this hypothesis, we co-cultured purified B cells with ALDHhigh CSCs with or without the addition of anti-PD-L1 mAb. We found that the reduction of IgG secretion of B cells suppressed by CSCs could be rescued by anti-PD-L1 in a dose-dependent manner. These experiments indicate that CSCs can directly suppress the IgG production by B cells via PD-L1/PD-1 interaction. Moreover, when we co-cultured purified B cells plus purified CD4+ Th cells with ALDHhigh CSCs with or without the addition of anti-PD-L1 mAb, we found that the IgG production was further and significantly (p=0.0155) reduced as compared to the co-culture of CSCs and B cells alone. The addition of anti-PD-L1 to the cultures rescued IgG production by T/B/CSC co-cultures to a greater (p=0.0429) extent than in just B/CSC co-culture. These results indicate that CSCs can also indirectly suppress IgG production by B cells via the PD-L1/PD-1 interaction with Th cells. Together, this study demonstrates that the anti-tumor function of anti-PD-L1 mAb involves host B cells, and that CSCs can both directly and indirectly inhibit B cell function through the PD-L1/PD-1 axis on both B cells and Th cells, respectively. Citation Format: Leiming Xia, FEI LIAO, Jing Zhang, Ming Lin, Ronald Herbst, Elaine Hurt, Alfred Chang, Max Wicha, Qiao Li. Involvement of B cells in the efficacy of anti-PD-L1 antibodies: Suppression of B cells by cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1676.