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].