B effector cells activated by a chimeric protein consisting of IL-2 and the ectodomain of TGF-β receptor II induce potent antitumor immunity

Cancer Res. 2012 Mar 1;72(5):1210-20. doi: 10.1158/0008-5472.CAN-11-1659. Epub 2012 Jan 12.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen-Presenting Cells / immunology*
  • B-Lymphocyte Subsets / immunology*
  • Cytotoxicity, Immunologic
  • Female
  • Gene Knockout Techniques
  • Humans
  • Interleukin-2 / immunology*
  • Lymphocyte Activation*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neoplasms, Experimental / immunology*
  • Recombinant Fusion Proteins / immunology

Substances

  • Interleukin-2
  • Recombinant Fusion Proteins