Secretable Chaperone Grp170 Enhances Therapeutic Activity of a Novel Tumor Suppressor, mda-7/IL-24
- 15 May 2008
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 68 (10), 3890-3898
- https://doi.org/10.1158/0008-5472.can-08-0156
Abstract
Melanoma differentiation–associated gene-7 (mda-7)/interleukin-24 (IL-24) is a cancer-specific, apoptosis-inducing gene with broad-spectrum antitumor activity, making it an ideal candidate for a novel cancer gene therapy. A systemic and sustained antitumor immune response generated at the time of initial molecular-targeted therapy would provide additional clinical benefits in cancer patients, resulting in improved prevention of tumor recurrence. In this study, we explored the therapeutic efficacy of intratumoral delivery of a nonreplicating adenoviral vector encoding mda-7/IL-24 (Ad.mda-7) and a secretable form of endoplasmic reticulum resident chaperone grp170 (Ad.sgrp170), a potent immunostimulatory adjuvant and antigen carrier. Intratumoral administration of Ad.mda-7 in combination with Ad.sgrp170 was more effective in controlling growth of TRAMP-C2 prostate tumor compared with either Ad.mda-7 or Ad.sgrp170 treatment. Generation of systemic antitumor immunity was shown by enhanced protection against subsequent tumor challenge and improved control of distant tumors. The combined treatments enhanced antigen and tumor-specific T-cell response, as indicated by increased IFN-γ production and cytolytic activity. Antibody depletion suggests that CD8+ T cells may be involved in the antitumor effect of the dual molecule–targeted therapies. Therefore, introducing immunostimulatory chaperone grp170 in situ strongly promotes the “immunogenic” cell death when delivered to the mda-7/IL-24–induced apoptotic tumor cells, indicating that an improved anticancer efficacy may be achieved by concurrently targeting both tumor and immune compartments. Given multiple undefined antigens present endogenously within prostate cancer, these data provide a rationale for combining sgrp170-based vaccine strategy with mda-7/IL-24–targeted cancer therapy to induce durable systemic immunity. [Cancer Res 2008;68(10):3890–8]Keywords
This publication has 39 references indexed in Scilit:
- Biological Response Determinants in HSV-tk + Ganciclovir Gene Therapy for Prostate CancerMolecular Therapy, 2006
- Immunoadjuvant chaperone, GRP170, induces ‘danger signals’ upon interaction with dendritic cellsImmunology & Cell Biology, 2006
- Melanoma differentiation-associated gene-7 (mda-7)/interleukin (IL)-24 induces anticancer immunity in a syngeneic murine modelCancer Gene Therapy, 2006
- Chaperoning Function of Stress Protein grp170, a Member of the hsp70 Superfamily, Is Responsible for its Immunoadjuvant ActivityCancer Research, 2006
- Glycoprotein 96–activated dendritic cells induce a CD8-biased T cell responseCell Stress and Chaperones, 2005
- Novel heat shock protein Hsp70L1 activates dendritic cells and acts as a Th1 polarizing adjuvantBlood, 2004
- HSP70 Peptide Binding Mutants Separate Antigen Delivery from Dendritic Cell StimulationImmunity, 2004
- The Chaperoning Properties of Mouse Grp170, a Member of the Third Family of Hsp70 Related ProteinsBiochemistry, 2003
- MDA-7 negatively regulates the β-catenin and PI3K signaling pathways in breast and lung tumor cellsMolecular Therapy, 2003
- The Induction of Tolerance by Dendritic Cells That Have Captured Apoptotic CellsThe Journal of Experimental Medicine, 2000