Natural killer (NK) cells attack and kill cancerous cells with decreased MHC class I expression.
NK cell activity is dependent on a balance of both activating and inactivating signals. Activating signals are regulated via NKG2D receptors located on the NK cell surface binding to ligands on the target cells. Inhibition is mediated by receptors on NK cells that bind to MHC class I molecules on healthy cells. Cancerous cells downregulate their expression of MHC class I molecules. Therefore, when the NK cell interacts with this transformed cell, the balance of activation-inactivation is tilted toward activation, activating NK cell to kill the target cell.
Markowitz and Bertagnolli review the molecular basis of colorectal cancer. The article reviews the multitude of factors that initiate the development of a tumor, drive its progression from polyp to cancer, and determine its responsiveness to antitumor agents. Among these factors include changes that promote genomic instability, inactivation of tumor suppressor genes, activation of oncogenes, and changes in growth factor pathways. Though there is a large body of research regarding these molecular factors, translating this data into clinically predictive and prognostic testing remains on the horizon.
Groh et al. demonstrate that tumor cells can secrete MIC, a MHC class I homologue, and that the subsequent binding of MIC [to NKG2D receptors on NK cells] may lead to endocytosis and degradation of NKG2D. This leads to decreased expression of NKG2D on the surface of NK cells and potentially decreased production of activation signals.
Illustration A demonstrates inactivated NK cells in the setting of normal MHC class I expression, activated NK cells in the setting of downregulated MHC class I expression, and activated NK cells in the setting of stress-induced cytokine production.
Answer 2: B-cells function to bind and present antigen to corresponding T-cells via MHC class II receptors. B-cells do not have direct cytotoxic effects.
Answer 3: Macrophages phagocytose cells upon opsonization with complement or by Fc receptors after specific opsonization by antibodies.
Answer 4: Eosinophils degranulate in the setting of allergies, asthma, and parasitic infections. Eosinophils do not have direct cytotoxic effects.
Answer 5: Cytotoxic T-cells, or CD8 T-cells, carry out their killing function when they recognize a specific antigen:MHC I complex on target cells.
Markowitz SD, Bertagnolli MM. Molecular origins of cancer: Molecular basis of colorectal cancer.N Engl J Med. 2009 Dec 17;361(25):2449-60.
PMID:20018966 (Link to Abstract)
Groh V, Wu J, Yee C, Spies T. Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature. 2002 Oct 17;419(6908)
PMID:12384702 (Link to Abstract)