Lipid A and its derivatives: the most mature tumor
immunostimulant
Mechanism of lipid A. Lipid A is the hydrophobic region
of lipopolysaccharide (LPS) (Fig.
4A), a glycolipid composed of the membrane of gram-negative bacteria,
recognized by Toll-like receptors 4 (TLR4) that highly observed in
immune cells, such as monocytes, macrophages, dendritic cells,
lymphocytes, and NK cells. Consequently, among all the TLR4 ligands,
lipid A is the most famous and studied one, which is the lipophilic
anchoring and main bioactive motif of LPS.
To be specific, the myeloid differentiation factor 88 (My88-dependent)
signaling pathway and the My88-independent signaling pathway were
involved in TLR4 activation by lipid A (Fig. 5). TLR4 can mediate
pathogen-associated molecular patterns (PAMPs), when TLR4 is activated
by lipid A and binds to myeloid differentiation factor 2 (MD2), the
signal is transduced to the toll or interleukin-1 receptor (TIR) domain.
Then interacting with toll or interleukin-1 receptor-domain-containing
adapter-inducing interferon-β (TRIF) and MyD88 to enable to activate
downstream signals [63]. Subsequently, various types of inflammatory
cytokine gene expressions is released as well as the maturation of the
immune cells, and signal transducer and activator of transcription play
important roles in mediating process [64]. The ultimate result is
the innate and adaptive immune responses [57].
Previous studies have shown that the continuous increase of inflammatory
factors may lead to the generation and persistence of chronic
inflammation microenvironment, and occasionally accelerate tumor growth
and tumor cell proliferation through autocrine pathways. Although the
potential of relying on humoral immunity to kill tumors is low,
effective cellular immunity can be activated by CTL, especially
CD8+ T cells, which can be activated in cancer
immunotherapy. And a massive of investigations demonstrated that a mouse
tumor model was treated with lipid A observed tumor regression [57].
In cancer immunotherapy, adjuvants have been successfully incorporated
into vaccine delivery with antigen to improve the bioactivity [5,
6]. Additionally, it is suggestable that TLR4 agonist like MPLA can
also as a safe and effective radio protector for clinical application
[65].