Alpha-alumina nanoparticles induce efficient autophagy-dependent cross-presentation and potent antitumour response

Therapeutic cancer vaccination is an attractive strategy because it induces T cells of the immune system to recognize and kill tumour cells in cancer patients. However, it remains difficult to generate large numbers of T cells that can recognize the antigens on cancer cells using conventional vaccine carrier systems. Here we show that α-Al(2)O(3) nanoparticles can act as an antigen carrier to reduce the amount of antigen required to activate T cells in vitro and in vivo. We found that α-Al(2)O(3) nanoparticles delivered antigens to autophagosomes in dendritic cells, which then presented the antigens to T cells through autophagy. Immunization of mice with α-Al(2)O(3) nanoparticles that are conjugated to either a model tumour antigen or autophagosomes derived from tumour cells resulted in tumour regression. These results suggest that α-Al(2)O(3) nanoparticles may be a promising adjuvant in the development of therapeutic cancer vaccines.

[1]  Ramon Arens,et al.  Recruitment of Antigen-Specific CD8+ T Cells in Response to Infection Is Markedly Efficient , 2009, Science.

[2]  O. Kepp,et al.  Autophagy within the antigen donor cell facilitates efficient antigen cross-priming of virus-specific CD8+ T cells , 2009, Cell Death and Differentiation.

[3]  D. Pardoll,et al.  Cancer vaccines. , 1993, Trends in pharmacological sciences.

[4]  G. Raposo,et al.  NOX2 Controls Phagosomal pH to Regulate Antigen Processing during Crosspresentation by Dendritic Cells , 2006, Cell.

[5]  P. van Endert,et al.  Fusion Proteins for Versatile Antigen Targeting to Cell Surface Receptors Reveal Differential Capacity to Prime Immune Responses , 2010, The Journal of Immunology.

[6]  Sai T Reddy,et al.  Exploiting lymphatic transport and complement activation in nanoparticle vaccines , 2007, Nature Biotechnology.

[7]  R. Lippé,et al.  Autophagy enhances the presentation of endogenous viral antigens on MHC class I molecules during HSV-1 infection , 2009, Nature Immunology.

[8]  W. Heath,et al.  Cross-presentation, dendritic cells, tolerance and immunity. , 2001, Annual review of immunology.

[9]  O. Finn,et al.  Cancer vaccines: between the idea and the reality , 2003, Nature Reviews Immunology.

[10]  R. Hunter,et al.  Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells , 2009, Nature Medicine.

[11]  B. Fox,et al.  Signaling through OX40 enhances antitumor immunity. , 2010, Seminars in oncology.

[12]  E. Latz,et al.  Getting closer to the dirty little secret. , 2011, Immunity.

[13]  P. Ricciardi-Castagnoli,et al.  Fcγ Receptor–mediated Induction of Dendritic Cell Maturation and Major Histocompatibility Complex Class I–restricted Antigen Presentation after Immune Complex Internalization , 1999, The Journal of experimental medicine.

[14]  Sven Burgdorf,et al.  Endocytosis mechanisms and the cell biology of antigen presentation. , 2008, Current opinion in immunology.

[15]  B. Guy,et al.  The perfect mix: recent progress in adjuvant research , 2007, Nature Reviews Microbiology.

[16]  Hidde L. Ploegh,et al.  The known unknowns of antigen processing and presentation , 2008, Nature Reviews Immunology.

[17]  W. Urba,et al.  Efficient cross-presentation depends on autophagy in tumor cells. , 2008, Cancer research.

[18]  Robert Rung,et al.  Oregon Nanoscience and Microtechnologies Institute , 2008 .

[19]  Peter Cresswell,et al.  Mechanisms of MHC class I‐restricted antigen processing and cross‐presentation , 2005, Immunological reviews.

[20]  Bali Pulendran,et al.  Immunological mechanisms of vaccination , 2011, Nature Immunology.

[21]  V. Crotzer,et al.  Autophagy and Its Role in MHC-Mediated Antigen Presentation1 , 2009, The Journal of Immunology.

[22]  T. Kreis,et al.  Translocation and clustering of endosomes and lysosomes depends on microtubules , 1987, The Journal of cell biology.

[23]  P. Marrack,et al.  Towards an understanding of the adjuvant action of aluminium , 2009, Nature Reviews Immunology.

[24]  J. Yewdell,et al.  Localization, quantitation, and in situ detection of specific peptide-MHC class I complexes using a monoclonal antibody. , 1997, Immunity.

[25]  Terje Johansen,et al.  p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death , 2005, The Journal of cell biology.

[26]  T. D. de Gruijl,et al.  Whole-cell cancer vaccination: from autologous to allogeneic tumor- and dendritic cell-based vaccines , 2008, Cancer Immunology, Immunotherapy.

[27]  Ping Zhang,et al.  Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity , 2011, Nature Medicine.

[28]  Ivan Dikic,et al.  A role for ubiquitin in selective autophagy. , 2009, Molecular cell.

[29]  西田 友哉 Discovery of Atg5/Atg7-independent alternative macroautophagy , 2010 .

[30]  R. Coffman,et al.  Vaccine adjuvants: putting innate immunity to work. , 2010, Immunity.