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B Effector Cells Activated by a Chimeric Protein Consisting of IL-2 and the Ectodomain of Tgfb Receptor II Induce Potent Antitumor Immunity

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B Effector Cells Activated by a Chimeric Protein Consisting of IL-2 and the Ectodomain of Tgfb Receptor II Induce Potent Antitumor Immunity Published OnlineFirst January 12, 2012; DOI: 10.1158/0008-5472.CAN-11-1659 Cancer Therapeutics, Targets, and Chemical Biology Research B Effector Cells Activated by a Chimeric Protein Consisting of IL-2 and the Ectodomain of TGFb Receptor II Induce Potent Antitumor Immunity Claudia Penafuerte1,2, Spencer Ng3,4, Norma Bautista-Lopez2, Elena Birman2, Kathy Forner2, and Jacques Galipeau2,4,5 Abstract We have previously shown that interleukin (IL)-2 receptor–expressing lymphoid cells stimulated with a chimeric protein linking IL-2 to the ectodomain of TGFb receptor II (also known as FIST) become resistant to TGFb-mediated suppression and produce significant amounts of proinflammatory cytokines. In this study, we have characterized the antigen presentation properties of FIST-stimulated B cells (hereafter inducible B effector cells, iBEC). FIST converts na€ve splenic B cells to B effector cells characterized by potent antigen presentation properties and production of TNFa and IFNg. iBECs display hyperphosphorylation of STAT3 and STAT5 downstream of the IL-2 receptor and upregulation of T-bet expression. iBECs maintain B-cell identity based on the expression of PAX5 and CD19 and overexpress Smad7, which confers resistance to TGFb-mediated suppression of B-cell activation. iBEC antitumor immunity was determined by a mouse model of lymphoma- expressing ovalbumin (E.G7-OVA) as a specific tumor antigen. OVA-pulsed iBECs function as antigen-presenting þ þ cells (APC) in vitro by inducing the activation of OVA-specific CD4 and CD8 T cells, respectively, and in vivo by conferring complete protective immunity against E.G7-OVA tumor challenge. In addition, OVA-pulsed iBECs promote tumor regression in immunocompetent C57Bl/6 mice bearing E.G7-OVA tumors. In conclusion, iBECs represent an entirely novel B cell–derived APC for immune therapy of cancer. Cancer Res; 72(5); 1–11. Ó2012 AACR. Introduction able from nonstem cell source with small amounts of periph- Antigen presentation is required for the development of eral blood. fi effective cell-mediated immunity (1). Dendritic cells (DC) have A new B-cell classi cation takes into account: (i) the pattern been extensively used as cellular adjuvants to present antigen of polarized cytokines produced by B cells, (ii) the cytokine in vivo (2, 3). Although highly effective in their ability to induce environment in which they were stimulated during their T cell–mediated immunity, the clinical applicability of DCs has primary encounter with antigens, and (iii) the T-cell subsets encountered several disadvantages. First, they are relatively they interact with. Two effector B-cell subsets have been fi fi rare in peripheral blood (<1% of leukocytes) and are therefore identi ed based on this classi cation system. The B cell usually isolated from leukapheresis or marrow sources (4). stimulated by TH1 effectors were coined B effector 1 (Be1) Second, they are comprised by a heterogeneous population cells and B cells stimulated by TH2 effectors are known as B with distinctive functions and third, they are difficult to expand effector 2 (Be2) cells (6). Be1 cells mainly produce TH1 cyto- in vitro from a nonstem cell source (5). As an alternative source kines [IFNg and interleukin (IL)-12], whereas Be2 produce TH2 of antigen-presenting cells (APC), B cells are reliably expand- cytokines (IL-4 and IL-5). The combination of antigen stimu- lation and interaction with polarized effector TH1 and TH2 cells dictate the differentiation of na€ve B cells toward IFNg or IL-4– producing cells capable of triggering a T 1orT 2 differenti- Authors' Affiliations: 1Department of Experimental Medicine, McGill Uni- H H versity; 2Lady Davis Institute for Medical Research, Montreal, Canada; ation program in na€ve T cells, respectively (6, 7). 3Emory University Graduate Program in Immunology and Molecular Path- Like DCs, B cells can process and present antigens in the ogenesis of the Graduate Division of Biological and Biomedical Sciences; fi þ Departments of 4Hematology and Medical Oncology and 5Pediatrics, context of MHC class II molecules and recruit speci c CD4 Emory University Winship Cancer Institute, Atlanta, Georgia T cell help, which in turns stimulates B-cell proliferation and differentiation (8, 9). In addition, B cells express high levels of Note: Supplementary data for this article are available at Cancer Research þ Online (http://cancerres.aacrjournals.org/). MHC class I and therefore act as APC for CD8 T cells, which Corresponding Author: Jacques Galipeau, Winship Cancer Institute, 1365 stimulates IL-2 production and cytotoxic T cells (CTL) activity Clifton Road, Atlanta, GA 30322. Phone: 404-778-1779; Fax: 404-778- (10, 11). It has also been shown that B cell–derived APCs are 1267; E-mail: [email protected] comparable with mature DCs in regards to presentation doi: 10.1158/0008-5472.CAN-11-1659 function in vivo (12). However, the method required to convert Ó2012 American Association for Cancer Research. and expand na€ve B cells to APCs requires coculture with www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2012 American Association for Cancer Research. Published OnlineFirst January 12, 2012; DOI: 10.1158/0008-5472.CAN-11-1659 Penafuerte et al. CD40L-expressing transfected cell lines or coculture with cytometers (BD) and analyzed by Cellquest software (BD) or T-helper cells (13), which may represent a substantial logistical Flow Jo. and regulatory obstacle to clinical translation of B cell–derived APCs in first-in-human use for immunotherapy purposes. Intracellular signaling, cytokine profile, and cell Here, we describe an entirely novel remedy to this conundrum proliferation which will allow further development of B cell–derived APCs as For signaling analysis, iBEC lysates were probed by Western a distinct APC for immunotherapy. blot with antiphosphorylated or antitotal STAT3, STAT1, We have previously shown that molecular genetic engineer- STAT5, BCL6, BLIMP-1, SMAD7, and PAX5 antibodies. Anti– ing of a fusion protein linking IL-2 to a TGFb decoy receptor b-tubulin and total protein antibodies were used as loading (14) adopts a hybrid IL-2-like cytokine function characterized controls. The concentration of cytokines produced by iBEC or by inhibition of TGF-b signaling and hyperactivation of IL-2 control-activated B cells (IL-5, IL-12, IL-17, IL-4, GM-CSF, signaling via STAT1. Here, we show that na€ve spleen-derived B TNFa, IFNg, and IL-6) was quantified by ELISA. The expression cells stimulated in vitro with FIST undergo a massive mitogenic of IFNg, IL-4, and IL-17 by CD19-positive cells was verified by response and adopt an entirely novel APC phenotype and flow cytometry with conjugated antibodies specific for each functional profile distinct from that previously described for cytokine. For T-bet, IFNg, IL-4, or IL-17 expression, iBEC or OT2 þ Be1-, Be2-, and CD40L-activated B cells. We further show that CD4 T cells were treated with Brefaldin A for 4 hours, these FIST-inducible B effector cells (iBEC) can lead to antigen- permeabilized, fixed, and stained with T-bet, IFNg, IL-4, or specific antitumor activity and immune protection against IL-17 conjugated antibodies or isotype controls for 1 hour. The tumor challenge in vivo. cell proliferation rate of iBECs by prestaining them with carboxyfluorescein succinimidyl ester (CFSE) and the percent- Materials and Methods age of proliferating cells were quantified by flow cytometry. Mice, reagents, and antibodies The data were analyzed by Cellquest software (Becton All experimental C57BL/6, transgenic mice (OT1 and OT2) Dickinson). þ þ and knockout mice (CD4 and CD8 T cell) were females of 6 In vitro to 8 weeks old (Jackson Laboratory). Antiphosphorylated and APC assay in vitro total length STAT3, STAT5, STAT1, BCL6, and BLIMP-1 anti- To assess the antigen presentation ability of iBECs , Â 4 bodies were obtained from Cell Signalling Technology; b-tubu- 1 10 B cells previously stimulated with FIST or control and lin and SMAD7 antibodies were obtained from Santa Cruz full-length ovalbumin (OVA)-pulsed B cells were washed 3 Â 5 þ þ Biotechnology. Anti-mouse FcR III/II, CD79b (BCR subunit), times and cocultured with 1 10 CD4 or CD8 T cells T-bet, IFNg, IL-4, IL-17, MHC class I and II, CD19, CD4, CD45R isolated from OT2 and OT1 mice, respectively. After 48 hours, (B220), CD24, CD22.2, CD43, CD279, CD138, CD27, CD80, CD86, the supernatants were collected to quantify the concentration CD25, CD69, CD23, CCR7, FasL, TRAIL, CD95, and CD40 and of IL-2 and IFNg by mouse enzyme-linked immunosorbent fl assay (ELISA) kits (R&D). The proliferation rates of OVA- the isotype control antibodies for ow cytometry were þ þ specific CD4 or CD8 T cells were determined by culturing obtained from BD Biosciences. þ þ CFSE prestained CD4 or CD8 T cells with OVA-pulsed iBEC B-cell isolation, generation, and phenotypic analysis of or control-stimulated B cells for 24 hours, and the percentage FIST-stimulated B cells of proliferating cells was quantified by flow cytometry. The B cells were isolated from splenocytes of immunocompetent data were analyzed by Cellquest software (Becton Dickinson). C57BL/6 by magnetic separation with the EasySep Mouse B Cell Isolation Kit (Stemcell Technologies) according to the iBEC cytotoxicity and iBEC-dependent induction of CTL manufacturer's recommendations. B-cell population purity activity and natural killer cell activation assessed by flow cytometry was 96%. FIST or control-stimu- A total of 5 Â 104 iBEC or control-activated B cells were lated B cells were generated by culturing B cells with 2 pmols cocultured with 5 Â 104 E.G7 or TUBO cells for 5 hours to carry per milliliter of FIST or controls (IL-2, sTbRII, and IL-2 plus out an in vitro nonradioactive cytotoxicity assay according to sTbRII) for 3 to 4 days at 37C.
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