Lymphocytes genetically modified to express tumor antigens target DCs in vivo and induce antitumor immunity
Vincenzo Russo, Arcadi Cipponi, Laura Raccosta, Cristina Rainelli, Raffaella Fontana, Daniela Maggioni, Francesca Lunghi, Sylvain Mukenge, Fabio Ciceri, Marco Bregni, Claudio Bordignon, Catia Traversari
Vincenzo Russo, Arcadi Cipponi, Laura Raccosta, Cristina Rainelli, Raffaella Fontana, Daniela Maggioni, Francesca Lunghi, Sylvain Mukenge, Fabio Ciceri, Marco Bregni, Claudio Bordignon, Catia Traversari
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Research Article Oncology

Lymphocytes genetically modified to express tumor antigens target DCs in vivo and induce antitumor immunity

Abstract

The exploitation of the physiologic processing and presenting machinery of DCs by in vivo loading of tumor-associated antigens may improve the immunogenic potential and clinical efficacy of DC-based cancer vaccines. Here we show that lymphocytes genetically modified to express self/tumor antigens, acting as antigen carriers, efficiently target DCs in vivo in tumor-bearing mice. The infusion of tyrosinase-related protein 2–transduced (TRP-2–transduced) lymphocytes induced the establishment of protective immunity and long-term memory in tumor-bearing mice. Analysis of the mechanism responsible for the induction of such an immune response allowed us to demonstrate that cross-presentation of the antigen mediated by the CD11c+CD8α+ DC subset had occurred. Furthermore, we demonstrated in vivo and in vitro that DCs had undergone activation upon phagocytosis of genetically modified lymphocytes, a process mediated by a cell-to-cell contact mechanism independent of CD40 triggering. Targeting and activation of secondary lymphoid organ–resident DCs endowed antigen-specific T cells with full effector functions, which ultimately increased tumor growth control and animal survival in a therapeutic tumor setting. We conclude that the use of transduced lymphocytes represents an efficient method for the in vivo loading of tumor-associated antigens on DCs.

Authors

Vincenzo Russo, Arcadi Cipponi, Laura Raccosta, Cristina Rainelli, Raffaella Fontana, Daniela Maggioni, Francesca Lunghi, Sylvain Mukenge, Fabio Ciceri, Marco Bregni, Claudio Bordignon, Catia Traversari

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Figure 3

Ex vivo analysis of OT-I and OT-II activation following vaccination with OVA-GMLs.

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Ex vivo analysis of OT-I and OT-II activation following vaccination with...
(A) Structure of the retroviral vector OVA-CSM. (B) Twenty-four hours after the infusion of CFSE-labeled OT-I T cells, mice were given mock-GMLs (Mock) or OVA-GMLs from WT (OVA WT) or β2m–/– (OVA β2m–/–) mice. Density dot plots (CFSE, left panels) show OT-I proliferation following treatments. Histograms show the expression of CD44 and downregulation of CD62L. (C) OT-I T cells from treated mice were restimulated in vitro with OVA257–264–loaded splenocytes and tested for IFN-γ release against pulsed or unpulsed RMA cells. In vitro–activated OT-I T cells were used as positive control. (D) Twenty-four hours after the infusion of CFSE-labeled OT-II T cells, mice were given mock- or OVA β2m–/–GMLs. Density dot plots show OT-II proliferation following treatment with OVA β2m–/– GMLs (CFSE, left panels). Histograms show the expression of CD44 and downregulation of CD62L. Data are representative of 3 (B) or 2 (D) experiments performed on splenocytes of 2 mice/group. (E) B16-OVA–bearing mice were transferred with OT-I T cells and then treated with mock- or OVA-GMLs from WT or β2m–/– mice. *P < 0.05, **P < 0.005; Student’s t test. (F) Mice adoptively transferred with OT-I T cells were challenged with mock- or OVA-GMLs from WT and β2m–/– mice. Forty days later, mice were challenged with B16-OVA cells and followed up. **P < 0.005, †P < 0.0005; Student’s t test. Data are representative of 3 (E) or 2 (F) experiments with 5 mice/group.