Role of Liver-Mediated Tolerance in Nanoparticle-Based Tumor Therapy

Abstract

In the last decades, the use of nanocarriers for immunotherapeutic purposes has gained a lot of attention, especially in the field of tumor therapy. However, most types of nanocarriers accumulate strongly in the liver after systemic application. Due to the default tolerance-promoting role of liver non-parenchymal cells (NPCs), Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs), and hepatic stellate cells (HSCs), their potential role on the immunological outcome of systemic nano-vaccination approaches for therapy of tumors in the liver and in other organs needs to be considered. Concerning immunological functions, KCs have been the focus until now, but recent studies have elucidated an important role of LSECs and HSCs as well. Therefore, this review aims to summarize current knowledge on the employment of nanocarriers for immunotherapeutic therapy of liver diseases and the overall role of liver NPCs in the context of nano-vaccination approaches. With regard to the latter, we discuss strategies on how to address liver NPCs, aiming to exploit and modulate their immunological properties, and alternatively how to avoid unwanted engagement of nano-vaccines by liver NPCs for tumor therapy.

Complement-Opsonized Nano-Carriers Are Bound by Dendritic Cells (DC) via Complement Receptor (CR)3, and by B Cell Subpopulations via CR-1/2, and Affect the Activation of DC and B-1 Cells

“…For numerous types of NC, considerable accumulation in the liver has been noted [ 24 ]. Besides Kupffer cells, which constitute the major liver-resident MAC population, also DC and LSEC, which exert immune functions as well, were reported to internalize NC [ 24 ].…”

“…For numerous types of NC, considerable accumulation in the liver has been noted [ 24 ]. Besides Kupffer cells, which constitute the major liver-resident MAC population, also DC and LSEC, which exert immune functions as well, were reported to internalize NC [ 24 ]. To delineate the potential of these cell types to bind NC in a complement-dependent manner, liver NPC (nonparenchymal cells) that comprise the aforementioned liver cell types were isolated and incubated with differentially pretreated NC.…”

“…It is tempting to speculate that besides the involvement of CR3 and CR4, respectively, other receptors may contribute to NC engagement. The latter holds true also for LSEC since this cell type is not known to express any CR [ 24 ] but showed elevated binding of carbohydrate-coated NC pretreated with native/h.i. serum.…”

“…More specifically, most in vitro studies on NC binding properties, which are performed as a prerequisite for subsequent in vivo testing, are performed using cell lines or primary immune cells that are rather easily accessible, like peripheral blood mononuclear cells (human) or splenic immune cells (mouse). However, in light of the frequent finding of strong NC accumulation in the liver in vivo, it may be of advantage to include liver NPC as well [ 24 ].…”

Enrichment Methods for Murine Liver Non-Parenchymal Cells Differentially Affect Their Immunophenotype and Responsiveness towards Stimulation

“…The liver is comprised of hepatocytes, which make up approximately two thirds of its total cell population and exert largely metabolic functions, comprising the synthesis of numerous types of plasma proteins—for example, albumin [ 4 ], fatty acids [ 5 ], carbohydrates [ 6 ], and bile acid metabolism [ 7 ]—but are also pivotal for detoxification [ 8 ]. The heterogeneous group of non-parenchymal cells (NPCs) plays an important role in immune regulation [ 9 ]. Liver NPCs comprise liver sinusoidal endothelial cells (LSECs, approximately 50% of NPCs), Kupffer cells (KCs, 20%) that largely constitute the resident macrophage population, and dendritic cells (DCs, 25%).…”