Very small size proteoliposomes abrogate cross-presentation of tumor antigens by myeloid-derived suppressor cells and induce their differentiation to dendritic cells

Abstract

Background: Myeloid-derived suppressor cells (MDSCs) are among the major obstacles that adjuvants for cancer vaccines have to overcome. These cells cross-present tumor-associated antigens (TAA) to naive T lymphocytes with a tolerogenic outcome. Very Small Size Proteoliposomes (VSSP) is used as adjuvant by four therapeutic cancer vaccines currently in Phase I and II clinical trials. We previously found that VSSP reduces the suppressive function of MDSCs, then activating antigen-specific CTL responses in tumor-bearing (TB) mice, with the consequent reduction of tumor growth. However the mechanistic explanation for the immunomodulatory effect of this adjuvant in TB hosts has not been addressed before. Methods: TB mice were inoculated with VSSP and MDSCs isolated and characterized by their expression of Arg1 and Nos2 genes by RT-PCR. The effect of VSSP on antigen cross-presentation by MDSCs, regulatory T cells (Tregs) expansion and MDSCs differentiation towards dendritic cells (DCs) was analyzed by FACS. Student's t test or ANOVA and Tukey's tests were used for statistical analyses.

Mitigating the prevalence and function of myeloid-derived suppressor cells by redirecting myeloid differentiation using a novel immune modulator

“…For example, prior work has shown that regulatory T cells are decreased in tumor-bearing mice treated with VSSP. 11 Additional mechanistic studies are warranted to delineate the relative contributions of these populations, as well as DC subsets impacted by treatment, toward the antitumor properties of VSSP. Moreover, the status and function of regulatory T cells and other immune suppressive populations in cancer patients treated with VSSP is an open area of investigation.…”

“…Previously, we showed that an immune modulator, known as VSSP ('very small sized particle'), can restore immune reactivity through its ability to abrogate MDSC function. [10][11][12] This novel agent consists of the GM3 ganglioside incorporated into the outer membrane vesicles of Neisseria meningitidis 13 that drives DC activation, antigen (Ag) cross-presentation and cytotoxic T lymphocyte induction. Currently, VSSP is being evaluated as a singleagent therapy and as an adjuvant in vaccine platforms for the treatment of advanced cancers, [14][15][16][17][18] including clinical studies presented here in renal cell carcinoma (RCC).…”

Myeloid-Derived Suppressor Cells in Solid Tumors

“…The differentiation of MDSCs into DCs or macrophages is achievable in many experiments. In vivo, Very Small Size Proteoliposomes (VSSP) were verified to differentiate MDSCs into phenotypically mature DCs, diminishing MDSCs immunosuppression effects in tumor-bearing mice [ 122 ]. All-trans retinoic acid (ATRA), a derivative of vitamin A, has a strong ability in inducing the differentiation of MDSCs into DCs and/or macrophages in vitro, primarily via the neutralization of high ROS production and up-regulating the protein level of glutathione synthase (GSS) in these cells [ 123 ].…”

Recent Advancements in Nanomedicine for ‘Cold’ Tumor Immunotherapy

“…Furthermore, regarding the blockade of MDSC recruitment, antagonists of chemokines (CCL2, CCL5, CSF-1, and G-CSF) and their receptors (CXCL2, CCR5, and CSF-1R) engaged in tumor chemotaxis of MDSCs have been identified as strategically promising therapeutic agents to inhibit MDSC migration to tumor lesions to restrict tumorigenesis [ 279 – 282 ], and most of these agents have been reported in previous clinical trials [ 283 ], e.g., phase II clinical trials on CXCR2 antagonist Reparixin for TNBC (NCT02370238) and phase 1 clinical trials on CCR5 antagonist Maraviroc for metastatic colorectal cancer (NCT01736813). Moreover, STAT3 inhibitor (AZD9150) [ 284 ], reactive nitrogen species (RNS) inhibitor (AT38) [ 285 ], nitroaspirin (NCX4060 and NCX4016) [ 286 ], phosphodiesterase-5 inhibitors (sildenafil) [ 287 , 288 ], triterpenoids (CDDO-Me) [ 246 ], COX-2 and PGE2 inhibitors (Celecoxib, ASA) [ 289 , 290 ], HDAC inhibitor (Entinostat) [ 291 ], and very-small-sized proteoliposomes (VVSP) [ 292 ] have effectively attenuated the potent immunosuppressive functions of MDSCs to reconstitute T cell responses and the success of immunotherapy. Finally, differentiation of suppressive MDSCs into mature myeloid cells (including macrophages and DCs) through treatment with Vitamin D3 [ 293 ], all-trans-retinoic acid (ATRA) [ 294 ], taxanes (docetaxel and paclitaxel) [ 295 ], TLR9 activation (CpG) [ 296 ], curcumin [ 297 ], whole-glucan particles (WGP) [ 298 ], and casein kinase inhibitor (tetrabromocinnamic acid) [ 299 ] can overtly modulates MDSCs and decrease the tumor growth in tumor-bearing mice and cancer patients.…”