Apolipoprotein A-I (ApoA-I)

Short Introduction of ApoA-I

ApoA-I may serve as a carrier for antigenic ligands such as phosphoantigens, either derived from the tumor cells themselves or the extracellular medium, thus permitting their "presentation" by a surface AS-related structure. It is the main protein component of High-Density Lipoproteins (HDL), widely known for regulating cholesterol trafficking and protecting against cardiovascular disease (CVD), which may also modulate inflammatory and immune responses. Key functions have been attributed to this protein, such as protection of endothelial function and clearance of the beta-amyloid (Aβ) peptide among others.

Fig.1 ApoA-I about high-density lipoprotein (HDL) biogenesis and reverse cholesterol transport (RCT). (Georgila, 2019)

ApoA-I and γδ T Cell

Modulation of Vγ9Vδ2 T cell activity by apo A-I could be due to apoA-I recognition by either the Vγ9Vδ2 TCR itself or by accessory receptors such as toll-like receptors which are known to be expressed on various conventional and non-conventional T cell subsets.

Like M5 monoclonal antibody (mAb), Vγ9Vδ2 TCR tetramers bind to the Vγ9Vδ2 target cells Daudi, K562, and RPMI 8226, but neither to Raji cells nor B lymphoblastoid cell lines. TCR tetramer binding to K562 was decreased when cells were cultured for 18h in the absence of serum and increased following the addition of serum or human apoA-I (hM5L or HDL-apoA-I).

This suggested that the effect of apoA-I was not merely due to non-specific adsorption of TCR tetramers, which might have been induced by hydrophobic compounds. Accordingly, neither serum nor apoA-I affected the binding of Vγ8Vδ3 TCR tetramers.

Fig.2 Vγ9Vδ2 TCR binding to tumor cells and apoA-I. (Scotet, 2005)

ApoA-I and Cancer

In a melanoma model, mice deficient for ApoA-I showed increased tumor burden and reduced survival. Conversely, transgenic overexpression of human ApoA-I or exogenous administration of ApoA-I protein reduced malignant burden, decreased metastases, and increased mouse survival. The tumor-suppressive activity of ApoA-I has also been demonstrated in an orthotopically implanted mouse model of pancreatic adenocarcinoma and a breast cancer mouse model, the latter being associated with a reduction in plasma oxLDL. Interestingly, dysfunctional, oxidized ApoA-I/HDL has been reported to promote breast cancer metastasis in mice. Other animal studies have reported an inverse association of serum ApoA-I levels with the progression of lung and gastric cancer in the mouse.

A study analyzing serum lipid profiles of patients diagnosed with any type of solid tumor and healthy controls showed decreased HDL/ApoA-I levels, specifically, in the cancer group. Similarly, relatively decreased levels of HDL/ApoA-I have been reported in many cancers of the gastrointestinal tract including adenocarcinomas of the stomach, the colon, the pancreas, and hepatocellular carcinoma (HCC). A serum proteomic analysis of patients with chronic liver disease associated with hepatitis C virus (HCV) infection showed that the development of HCC was associated with lower levels of ApoA-I. Also, relatively reduced serum HDL/ApoA-I levels have been found in patients with lung and breast adenocarcinoma, early-stage ovarian and cervical cancer, and acute lymphoblastic leukemia.

Table.1 Clinicopathologic association of Apo A-I in cancer. (Georgila, 2019)

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References

1. Georgila, Konstantina.; et al. Apolipoprotein A-I (ApoA-I), Immunity, Inflammation, and Cancer. Cancers. 2019, 11(8).
2. Scotet, E.; et al. Tumor Recognition following Vγ9Vδ2 T Cell Receptor Interactions with a Surface F1-ATPase-Related Structure and Apolipoprotein A-I. Immunity. 2005, (22): 71-80.