Tumoricidal Effects of Hepatic NK Cells
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Tumoricidal Effects of Hepatic NK Cells

The liver is a major site for the formation and metastasis of Tumors. Malignant Liver Tumors fall into two types: Primary and Metastatic. While Primary Liver tumors such as HCC (Hepatocellular Carcinoma) originate in the liver itself, Metastatic or Secondary Liver Tumors commpnly known as “Liver Metastases” are cancerous tumors that originate at sites remote from the liver and spread to the liver via the bloodstream. As filtration of blood is one of the main functions of Liver, cancer cells from other parts of the body have easy access to the Liver. It provides a fertile platform in which Metastases can establish, not only because of its rich, dual blood supply but also because of humoral factors that promote cell growth. Metastasis is the most common neoplasm in an adult Liver, and the Liver is the second most common site for metastatic spread, after the Lymph Nodes. It therefore becomes essential for the host immune status in the Liver, particularly natural immune responses to control the dissemination and growth of Metastatic tumors. This is achieved by the intervention of the hepatic NK (Natural Killer) cells, which have the ability to mediate spontaneous cytotoxicity both against the intrinsic Tumor cells and metastases, and thus participate in the innate immune response against Tumor cells in vivo (Ref.1 & 2).

The liver is a complex organ composed of hepatic parenchymal cells and a variety of non-parenchymal cells that consist of Hepatocytes, Endothelial cells (also known as LSECs (Liver Sinusoidal Endothelial Cells)), Kupffer cells, and several subsets of resident lymphocytes, including NK Cells/Pit cells and T-cells (Tumor Metastases). When a Tumor cell enters the Liver Sinusoid, it is mechanically trapped and/or adheres to LSECs. The NK cells are located in the Hepatic Sinusoid, adhering to the LSECs, and are thus in a strategic position to kill arriving metastasizing Tumor cells. The NK cells adhere to Tumor cells by adhesion molecules like LFA1 (Lymphocyte Function-Associated Antigen-1), which are recognized by their receptor ICAM1 (Intercellular Adhesion Molecule-1) expressed on the Tumor cell surface (Ref.3 & 4).

Several mechanisms contribute to the antitumor effects of the effector NK cells. The two most potent effector mechanisms used by these cell types are: i) the triggering of the Fas-mediated death pathway by the ligation of FasL (Fas Ligand) on effector cells with cell surface Fas on target Tumor cells, or ii) the use of the Perforin-Granzyme cell death pathway, which is focused to the site of effector-target interaction and mediates apoptosis of the target cell (the Tumor cell). Thus, the NK cells use the FasL and the Perforin-Granzyme pathway to kill the target cells (Ref.2, 3 & 5). FasL on NK cells binds Fas present on the target Tumor cell membrane, which results in oligomerization of Fas and activation of Caspase8. sFas (Soluble Fas) produced by hepatocytes blocks FasL on the NK cells, preventing possible harmful effects on the FasL-sensitive LSECs and hepatocytes. Stimulation of the Fas receptor results in recruitment and activation of the initiator Caspase, Caspase8, through interaction with the adaptor molecule FADD (Fas-Associated Death Domain Protein). Caspase8 activation results in the activation of Caspase Cascade either directly, or through a mitochondrion-dependent pathway. Caspases play a central role in the execution of Apoptosis of the invading Tumor cell (Ref.5).

Perforin and Granzymes, of which Granzyme-B is the most potent, reside in granules presnt in the cytosol of hepatic NK cells and are released by exocytosis. Perforin and Granzyme-B, as a complex with SG (Serglycin) as a scaffold, are released by granule exocytosis in the space formed between the NK Cell-Tumor conjugate. The Serglycin-Perforin -Granzyme-B complex is taken up into the Tumor cell by endocytosis through the receptor M6PR (Mannose-6-Phosphate Receptor). Perforin then acts to release Granzyme-B that is sequestered in an Endosome into the cytosol of the target cell. Intracellular delivery of Granzyme-B results in the initiation of pathways leading to the Tumor cell death. It initiates proteolytic activation of Caspase Cascade by direct activation of Caspase3 or indirectly through Caspase8; or through a mitochondrion-dependent pathway. Granzyme-B mainly triggers Caspase activation indirectly. It achieves this by cleavage of the pro-apoptotic ‘BH3-only’member of the BCL2 ((B-Cell CLL/Lymphoma-2) family, BID (BH3-Interacting Domain Death Agonist), which results in its translocation, with other members of the BCL2-family such as BAX (BCL2 Associated-X Protein), to the mitochondria. This prompts CytoC (Cytochrome-C) release and the activation of Caspase9 through interaction with the adaptor molecule APAF1 (Apoptotic Protease-Activating Factor-1). Caspase9 in turn, activates the downstream Caspases, such as Caspase3, Caspase6, and Caspase7 culminating in Apoptosis. On the other hand, CytoC release causes mitochondrial dysfunction which leads to the release of factors such as AIF (Apoptosis-Inducing Factor) and EndoG (Endonuclease-G), which mediate Caspase-independent cell death by causing DNA damage. Granzyme-B causes direct activation of DFF40/CAD (DNA Fragmentation-40/Caspase-Activated Deoxynuclease)—which leads to proteolysis of the inhibitor ICAD (Inhibitor of CAD), and damages the DNA of the Tumor cell. DNA damage can also be brought about by Caspase3 through CAD activation. Cytolysis by Cr (Chromium) release is induced by Granzyme-B in a Caspase-independent mechanism. All these events lead to death of the invading Tumor cell (Ref.6, 7 & 8).

Damage of Liver cells other than the Tumor cells e.g. Hepatocytes, and LSECs that might be caused by leakage of Granzyme-B-Perforin is prevented by the very efficient endocytic uptake of the Granzyme-B-Serglycin-Perforin complex by the HARs (Hyaluronic Acid Rweceptors) expressed on LSECs. LSECs and the NK cells themselves are protected from the action of Granzyme-B by strong expression of the endogenous Granzyme-B inhibitor PI9 (Protease inhibitor-9). PI9 might also be expressed aberrantly by some cancer cells to disrupt the Apoptotic pathways stimulated by Granzyme-B. The Tumor cells having diminished MHC-I (Major Histocompatibility Complex Class-I) expression, are particularly vulnerable for NK cell-mediated killing. Hepatic NK cells are thus, capable of mediating spontaneous cytotoxicity against Tumor cells and their metastases when they lose or have diminished MHC-Iexpression. Downregulation of MHC-I-binding inhibitory receptors expressed on the NK cells can also facilitate Tumour rejection by the hepatic immune system (Ref.9, 10, 11 & 12).