Natural killer cells were originally identified
by their ability to kill tumor cells.
We now know that there are tumor infiltrating
natural killer cells that enter into tumors.
They respond to stress
or abnormal cells.
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.
The activating receptors send signals into the
cell, and so do the inhibitory receptors.
Tumors for a variety of reasons
often stop expressing MHC Class I.
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.
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.
And there is a lack of stimulation through the
inhibitory receptors, because they recognize Class I.
If there’s no Class I, there can’t be any
stimulation through the inhibitory receptors.
And the major response is through the activating receptor
which activates the NK cell to kill the tumor cell.
However, some tumor cells will maintain expression of MHC Class
I but up-regulate the ligands for the activating receptors.
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.
And therefore again, the natural
killer cell can kill the tumor cell.
With regard to T-cell recognition of tumor antigens,
most tumor cells have around about 60 or more mutations.
Each patient has a
unique set of mutations.
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.
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.
And therefore the
lymphocytes are tolerant.
They also exhibit a Darwinian selection
of tumor antigen loss mutants.
So the immune system may recognize something, may start to
attack this abnormal protein on the surface of the tumor cell.
But remember, tumor cells are dividing,
dividing, dividing incredibly rapidly.
It just requires one cell to lose
expression of that tumor antigen.
And that will have a selective
advantage because the immune system
can no longer recognize it, and it
will become the dominant clone.
They may fail to produce damage
associated molecular patterns.
And they can have reduced
expression of MHC molecules.
A number of pathogens that induce tumors actually interfere
with antigen processing and presentation pathways.
The Epstein-Barr virus is
an excellent example here.
Tumors have low levels of co-stimulatory
molecules for example, the B7 molecules.
And therefore induce T-cell anergy.
They can up-regulate the anti-apoptotic gene, Bcl-2
to resist killing by cytotoxic T-lymphocytes.
And they can produce
For example, transforming growth factor beta, vascular
endothelial growth factor and
indoleamine-2,3-dioxygenase or IDO.