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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2012-03, Vol.72 (5), p.1210-1220
• Main Authors: PENAFUERTE, Claudia, NG, Spencer, BAUTISTA-LOPEZ, Norma, BIRMAN, Elena, FORNER, Kathy, GALIPEAU, Jacques
• Format: Article
• Language: English
• Subjects: Animals; Antigen-Presenting Cells - immunology; Antineoplastic agents; B-Lymphocyte Subsets - immunology; Biological and medical sciences; Cytotoxicity, Immunologic; Female; Gene Knockout Techniques; Humans; Interleukin-2 - immunology; Lymphocyte Activation; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neoplasms, Experimental - immunology; Pharmacology. Drug treatments; Recombinant Fusion Proteins - immunology; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-11-1659

We have previously shown that interleukin (IL)-2 receptor-expressing lymphoid cells stimulated with a chimeric protein linking IL-2 to the ectodomain of TGF-β receptor II (also known as FIST) become resistant to TGF-β-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 naïve splenic B cells to B effector cells characterized by potent antigen presentation properties and production of TNFα and IFNγ. 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 TGF-β-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 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.