Abstract 487: Effector B cells in cancer adoptive immunotherapy.

Abstract

Abstract Successful anti-cancer treatment will have to appropriately stimulate both humoral as well as cellular immunity. To test this hypothesis, we reported that simultaneous targeting of CD3 on T cells and CD40 on B cells augmented the antitumor reactivity of tumor-primed LN cells. These studies established a role for engaging CD40 on tumor-draining lymph node (TDLN) B cells in the generation of effector cells. We also reported that IL-21 augmented the efficacy of T cell therapy by eliciting concurrent cellular and humoral responses. This study confirmed an interactive role between tumor-specific humoral responses related to IL-21 administration and adoptively transferred effector T cells. In recent study, we identified TDLN B cells as effector cells in an adoptive immunotherapy model. In vivo primed and in vitro activated TDLN B cells alone mediated effective (p<0.05) tumor regression after adoptive transfer into two histologically distinct murine tumor models. B cell plus T cell transfers resulted in substantially more efficient antitumor responses than B cells or T cells alone (p<0.05). Activated TDLN B cells produced IgM, IgG and IgG2b, which bound specifically to tumor cells and led to specific tumor cell lysis in the presence of complement. In a third tumor model, the 4T1 breast cancer spontaneous metastases model, we found that adoptive transfer of activated 4T1 TDLN B cells alone mediated significant inhibition of spontaneous metastases of the 4T1 cells from the injection site (the mammary fat pad) to the lung. Examination of the host revealed that the adoptive transfer of these B cells resulted in the induction of tumor specific T cell immunity as measured by cytotoxicity and cytokine (IFNγ and GM-CSF) production. Importantly, we found that the 4T1 TDLN effector B cells could directly and specifically kill the 4T1 tumor cells in the absence of antibody. More mechanistic studies revealed that adoptively transferred IL-10−/- TDLN B cells mediated significantly more effective antitumor immunity than equal numbers of WT TDLN B cells (p<0.05). Adoptively transferred IL-10−/− 4T1TDLN B cells increased the production of IgG which bound to 4T1 tumor cells and significantly increased CTL activity mediated by host B cells as well as T cells in an immunologically specific fashion. While the role played by B cells in the host immune response to cancer is complex and controversial, our results indicate that in vivo primed and in vitro activated TDLN B cells can function as effector cells in cancer adoptive immunotherapy, and removal of IL-10-producing B cell subsets may represent an effective strategy to augment the therapeutic efficacy of the TDLN effector B cells in cancer adoptive immunotherapy. Citation Format: Huimin Tao, Lin Lu, Martin Egenti, Alfred E. Chang, Qiao Li. Effector B cells in cancer adoptive immunotherapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 487. doi:10.1158/1538-7445.AM2013-487