GM3-containing nanoparticles in immunosuppressed hosts: Effect on myeloid-derived suppressor cells

Abstract

Cancer vaccines to date have not broadly achieved a significant impact on the overall survival of patients. The negative effect on the immune system of the tumor itself and conventional anti-tumor treatments such as chemotherapy is, undoubtedly, a key reason for these disappointing results. Myeloid-derived suppressor cells (MDSCs) are considered a central node of the immunosuppressive network associated with tumors. These cells inhibit the effector function of natural killer and CD8⁺ T cells, expand regulatory T cells and can differentiate into tumor-associated macrophages within the tumor microenvironment. Thus, overcoming the suppressive effects of MDSCs is likely to be critical for cancer immunotherapy to generate effective anti-tumor immune responses. However, the capacity of cancer vaccines and particularly their adjuvants to overcome this inhibitory population has not been well characterized. Very small size proteoliposomes (VSSP) is a nanoparticulated adjuvant specifically designed to be formulated with vaccines used in the treatment of immunocompromised patients. This adjuvant contains immunostimulatory bacterial signals together with GM3 ganglioside. VSSP promotes dendritic cell maturation, antigen cross-presentation to CD8⁺ T cells, Th1 polarization, and enhances CD8⁺ T cell response in tumor-free mice. Currently, four cancer vaccines using VSSP as the adjuvant are in Phase I and II clinical trials. In this review, we summarize our work characterizing the unique ability of VSSP to stimulate antigen-specific CD8⁺ T cell responses in two immunocompromised scenarios; in tumor-bearing mice and during chemotherapy-induced leukopenia. Particular emphasis has been placed on the interaction of these nanoparticles with MDSCs, as well as comparison with other cancer vaccine adjuvants currently in preclinical or clinical studies.

Keywords: Very small size proteoliposomes, Adjuvants, Tumors, Myeloid-derived suppressor cells, Leukopenia, Chemotherapy

Core tip: Very small size proteoliposomes (VSSP) is a nanoparticulated adjuvant being used in the formulation of several cancer vaccines that are currently in clinical trials. In this review we summarize the unique ability of VSSP to stimulate antigen-specific CD8⁺ T cell responses in tumor-bearing mice and in mice with chemotherapy-induced leukopenia, both immunosuppressive scenarios frequently found in cancer patients. As a possible mechanism of this efficacy, we have focused on the modulation of myeloid-derived suppressor cells (MDSCs) by these nanoparticles, in the context of the current knowledge about the interaction of cancer vaccine adjuvants with MDSCs.