Regulatory B10 Cell Depletion Inhibits MC38 Colon Cancer Growth In Vivo
Yasuhiro Fujisawa1,2, Jacqueline Lykken1, Manabu Fujimoto2, Thomas F. Tedder1 1Department of Immunology, Duke University, USA; 2Derpartment of Dermatology, University of Tsukuba, Japan
Regulatory B cells with the capacity to produce interleukin 10 (IL-10, B10 cells) restrain inflammation and immune responses. By contrast, B10 cell depletion enhances adaptive, cellular, humoral and innate immunity in vivo. The therapeutic potential of preferential B10 cell depletion using MB22-10 monoclonal antibody (mAb) was therefore tested alone in vivo and in combination with established immune checkpoint inhibitors to determine whether targeting B10 cells represents a mechanistically novel immunotherapeutic pathway. MC38 colon adenocarcinoma tumor growth and C57BL/6 mouse survival were monitored after prophylactic and therapeutic treatments with MB22-10, CD20 (MB20-11), PD-1 (RMP1-14), and CTLA-4 (9H10) mAbs or following regulatory T cell (Treg) depletion using denileukin diftitox (Ontak, Eisai). Mature B cell depletion using CD20 mAb did not affect tumor growth, while preferential B10 cell depletion inhibited MC38 growth. Tumor rejection was also accelerated in mice depleted of B10 cells alone and in combination with PD-1 or CTLA-4 mAbs in all models. Remarkably, B10 cell depletion in combination with PD-1 and CTLA-4 mAb treatments lead to complete regression of established tumors in ~60% of mice, a significant increase (P<0.001) relative to PD-1 plus CTLA-4 mAb treatments. B10 cell plus Treg cell depletion also had potent synergistic effects relative to singular therapies. Moreover, B10 cell depletion, PD-1 and CTLA-4 mAb treatments led to CD4+ and CD8+ T cell activation within the spleen and lymph nodes of mice without tumors, with the combination of treatments resulting in optimal T cell activation. Thus, while B10 cell depletion offers an effective monotherapy, its synergistic effects with clinically effective checkpoint inhibitors provides an exciting immunotherapeutic option for enhancing current checkpoint inhibitor therapies.
(Supported by Sponsored Research Agreement with Cellective BioTherapy, Inc.)
Credits: None available.
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