Tumor-Infiltrating NK Cells

00:01 Natural killer cells were originally identified by their ability to kill tumor cells.

00:08 We now know that there are tumor infiltrating natural killer cells that enter into tumors.

00:15 They respond to stress or abnormal cells.

00:20 And the balance of the activating and inhibitory receptors determines the outcome of an encounter with a natural killer cell. So natural killer cells have on their cell surface a mixture of activating and inhibitory receptors. They’ll have several activating receptors and several inhibitory receptors. The inhibitory receptors recognize MHC Class I which is present on the cell surface of all normal cells. The activating receptors recognize a number of different molecules that are also normally present on all normal cells.

01:04 The activating receptors send signals into the cell, and so do the inhibitory receptors.

01:16 Tumors for a variety of reasons often stop expressing MHC Class I.

01:24 And because this is a molecule that is normally present on all nucleated cells, the natural killer cells have learnt to recognize the absence of MHC Class I which we often refer to as missing self.

01:38 These NK cells can recognize that as being a marker that something weird is going on, something abnormal is going on with this cell, perhaps it’s a tumor cell.

01:48 And there is a lack of stimulation through the inhibitory receptors, because they recognize Class I.

01:54 If there’s no Class I, there can’t be any stimulation through the inhibitory receptors.

01:58 And the major response is through the activating receptor which activates the NK cell to kill the tumor cell.

02:05 However, some tumor cells will maintain expression of MHC Class I but up-regulate the ligands for the activating receptors.

02:16 So although there is still an inhibitory signal going into the NK cell, there is a much more powerful signal coming from the activating receptors which overrides the inhibitory signal.

02:28 And therefore again, the natural killer cell can kill the tumor cell.

02:34 With regard to T-cell recognition of tumor antigens, most tumor cells have around about 60 or more mutations.

02:43 Each patient has a unique set of mutations.

02:48 For cytotoxic T-cell recognition of mutated antigen, the antigen must be processed by the proteasome, and a peptide containing the mutated amino acid sequence must bind to the patient’s MHC Class I molecules.

03:04 So given all these potential ways in which the immune system can fight tumor cells, why is it that tumors do not usually succumb to the immune response? Well, tumors share most antigens with the normal cell type from which they arose.

03:24 And therefore the lymphocytes are tolerant.

03:28 They also exhibit a Darwinian selection of tumor antigen loss mutants.

03:34 So the immune system may recognize something, may start to attack this abnormal protein on the surface of the tumor cell.

03:40 But remember, tumor cells are dividing, dividing, dividing incredibly rapidly.

03:45 It just requires one cell to lose expression of that tumor antigen.

03:50 And that will have a selective advantage because the immune system can no longer recognize it, and it will become the dominant clone.

03:58 They may fail to produce damage associated molecular patterns.

04:04 And they can have reduced expression of MHC molecules.

04:08 A number of pathogens that induce tumors actually interfere with antigen processing and presentation pathways.

04:16 The Epstein-Barr virus is an excellent example here.

04:19 Tumors have low levels of co-stimulatory molecules for example, the B7 molecules.

04:24 And therefore induce T-cell anergy.

04:26 They can up-regulate the anti-apoptotic gene, Bcl-2 to resist killing by cytotoxic T-lymphocytes.

04:35 And they can produce immunosuppressive molecules.

04:38 For example, transforming growth factor beta, vascular endothelial growth factor and indoleamine-2,3-dioxygenase or IDO.