Antitumor immunity in cancer patients is heavily modulated by cells of the innate immune system. Antigen-presenting cells, including dendritic cells, macrophages, and B cells, initiate immune recognition of tumor antigen by displaying antigen to effector cells. Countering this immune stimulation are immunosuppressive cells which include M2 macrophages, N2 neutrophils, and myeloid-derived suppressor cells (MDSCs). To create effective cancer immunotherapies, it is critical that we can target these important cell types of the immune system with immunostimulatory compounds. A commonality of these cell types is the complement receptor, which recognizes pathogens that are bound to activated complement C3 in human blood. To target the complement receptor, we have created a liposome that has a small molecule, orthopyridyl disulfide (OPSS), conjugated to its surface. OPSS forms a disulfide bond with activated complement C3, which then targets liposomes for uptake by dendritic cells, macrophages, B cells, MDSCs, and neutrophils in human blood. Internalization is efficient and specific to cells that display the complement receptor. Liposomes are a versatile drug delivery device. Possible applications for this system include delivery of toll-receptor agonists or tumor antigen to antigen-presenting cells and delivery of immunostimulatory drugs to M2, N2, and MDSC immunosuppressive cells.

Antigen presenting cells (APCs) initiate the immune response against cancer by engulfing and presenting tumor antigen to T cells. Our lab has recently developed a liposomal nanoparticle that binds complement C3 proteins, allowing it to bind to the complement C3 receptors of APCs and directly deliver antigenic peptides. APCs were shown to internalize and process complement C3bound liposomes containing ovalbumin (OVA), resulting in a significant increase in activated T cells that recognize OVA. Mice bearing A20-OVA lymphoma tumors were treated with OVAloaded C3-liposomes, which led to reduced tumor growth in both treated and distal tumors in all mice. Peripheral blood from treated mice had a lower percentage of immunosuppressive myeloid derived suppressor cells (MDSCs), a higher percentage of B cells, and increased anti-OVA IgG 1 levels compared to control mice. These results indicate that C3-liposome delivery of tumor antigen to APCs initiates a potent and systemic antitumor immune response.

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In the tumor microenvironment, cytokines, growth factors, and oncogenes mediate constitutive activation of the signal transducer and activator of transcription 3 (STAT3) signaling pathway in both cancer cells and infiltrating immune cells. STAT3 activation in cancer cells drives tumorigenic changes that allow for increased survival, proliferation, and resistance to apoptosis. The modulation of immune cells is more complicated and conflicting. STAT3 signaling drives the myeloid cell phenotype towards an immune suppressive state, which mediates T cell inhibition. On the other hand, STAT3 signaling in T cells leads to proliferation and T cell activity required for an anti-tumor response.Targeted delivery of STAT3 inhibitors to cancer cells and myeloid cells could therefore improve therapeutic outcomes. Many compounds that inhibit the STAT3 pathways for cancer treatment include peptide drugs, small molecule inhibitors, and natural compounds. However, natural compounds that inhibit STAT3 are often hydrophobic, which reduces their bioavailability and leads to unfavorable pharmacokinetics. This review focuses specifically on liposome-encapsulated natural STAT3 inhibitors and their ability to target cancer cells and myeloid cells to reduce tumor growth and decrease STAT3-mediated immune suppression. Many of these liposome formulations have led to profound tumor reduction and examples of combination formulations have been shown to eliminate tumors through immune modulation.