Abstract 4840: Blockade of IL-10 production in effector B cells significantly increases their therapeutic efficacy in cancer adoptive immunotherapy

Abstract

Abstract We have previously reported the antitumor reactivity of adoptively transferred effector B cells and the mechanisms by which they mediate tumor regression in a spontaneous metastasis model. 4T1 breast cancer cells were inoculated into syngeneic Balb/c mice to prime tumor-draining lymph node (TDLN). TDLNs were subsequently harvested and B cells activated ex vivo. When adoptively transferred into mice inoculated with 4T1 tumor in the mammary fat pad, these activated B cells alone mediated the inhibition of spontaneous metastases to the lung. In this study, we used IL-10−/− Balb/c mice to generate IL-10−/− TDLN, and evaluated the antitumor immunity of IL-10−/− TDLN B cells. Adoptively transferred IL-10−/− TDLN B cells mediated significantly more effective antitumor immunity than equal numbers of WT TDLN B cells (p<0.05). Activated IL-10−/− effector 4T1 TDLN B cells were capable of killing 4T1 tumor cells in a tumor antigen specific manner in in vitro cytotoxicity assays independent of antibody and complement. Adoptive transfer of IL-10−/− TDLN B cells resulted in the induction of host T and B cell antitumor immunity significantly more than adoptive transfer of WT TDLN B cells (p<0.05). This was evident by significantly modulated cytokine production (e.g. up-regulated IFN-gamma and IL-2 production by host T cells, but down-regulated IL-10 production by host B cells). In addition, adoptively transferred IL-10−/− TDLN B cells increased the production of IgG which bound to 4T1 tumor cells. Furthermore, IL-10−/− TDLN B cell infusion significantly increased tumor cell lysis (CTL) activity mediated by host B cells as well as T cells in an immunologically specific fashion. The molecular and cellular pathways involved in the direct killing of 4T1 tumor cells by IL-10−/- 4T1 TDLN effector B cells and by host B cells subjected to IL-10−/- 4T1 TDLN effector B cell adoptive transfer is under active investigation in our lab. While the role played by B cells in the host immune response to cancer is complex and controversial, our results indicate that removal of IL-10-producing B cell subsets may represent an effective strategy to augment the therapeutic efficacy of TDLN B cells used in adoptive immunotherapy. Mechanistically, adoptive transfer of B cells depleted of IL-10-producing subsets destroys tumor cells directly and confers greater host cellular and humoral antitumor immunity by shifting cytokine production to a Type 1 profile and by producing tumor-reactive antibodies respectively. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4840. doi:1538-7445.AM2012-4840