Direct incorporation of the NKT-cell activator α-galactosylceramide into a recombinant Listeria monocytogenes improves breast cancer vaccine efficacy

• Published in: British journal of cancer 2014-11, Vol.111 (10), p.1945-1954
• Main Authors: Singh, M, Quispe-Tintaya, W, Chandra, D, Jahangir, A, Venkataswamy, M M, Ng, T W, Sharma-Kharkwal, S, Carreño, L J, Porcelli, S A, Gravekamp, C
• Format: Article
• Language: English
• Subjects: 631/250/24/590/2291; 692/699/67/1059/2325; 692/699/67/1347; Animals; Antigens, Neoplasm - immunology; Apoptosis; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Blotting, Western; Cancer Research; Cancer Vaccines - therapeutic use; Cell Adhesion; Cell Cycle; Cell Movement; Cell Proliferation; Drug Resistance; Epidemiology; Female; Flow Cytometry; Galactosylceramides - metabolism; Gynecology. Andrology. Obstetrics; Immunoenzyme Techniques; Immunotherapy; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Killer Cells, Natural - pathology; Listeria monocytogenes; Listeria monocytogenes - genetics; Lymphocyte Activation; Mammary gland diseases; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - immunology; Mammary Neoplasms, Experimental - pathology; Mammary Neoplasms, Experimental - prevention & control; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Medicine; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Metastasis; Neoplasm Proteins - genetics; Oncology; Real-Time Polymerase Chain Reaction; Recombination, Genetic; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes - pathology; Translational Therapeutics; Tumor Cells, Cultured; Tumors; Vaccination
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2014.486

Background: Immune suppression in the tumour microenvironment remains a major limitation to successful immunotherapy of cancer. In the current study, we analysed whether the natural killer T cell-activating glycolipid α -galactosylceramide could overcome immune suppression and improve vaccination against metastatic breast cancer. Methods: Mice with metastatic breast cancer (4T1 model) were therapeutically treated with a Listeria monocytogenes -based vaccine expressing tumour-associated antigen Mage-b followed by α -galactosylceramide as separate agents, or as a complex of α -galactosylceramide stably incorporated into Listeria -Mage-b. Effects on metastases, tumour weight, toxicity and immune responses were determined. Results: Sequential treatments of mice with established 4T1 breast carcinomas using Listeria -Mage-b followed by α -galactosylceramide as a separate agent was highly effective at reducing metastases, but was accompanied by severe liver toxicity. In contrast, combined therapy using Listeria -Mage-b modified by incorporation of α -galactosylceramide resulted in nearly complete elimination of metastases without toxicity. This was associated with a significant increase in the percentage of natural killer T cells in the spleen, and an increase in natural killer cell activity and in T cell responses to Mage-b. Conclusions: Our results suggest that direct incorporation of α -galactosylceramide into a live bacterial vaccine vector is a promising non-toxic new approach for the treatment of metastatic breast cancer.