I am Soldano Ferrone,
and I hold a faculty position at the Massachusetts General Hospital,
Harvard Medical School in Boston, Massachusetts, United States.
My research interest in the area of tumor immunology,
and especially in the mechanisms which are utilized by tumor cells
in order to escape recognition and destruction by the host immune system.
Over the years, I have investigated
how tumor cells change the expression of HLA class I and class II antigens
and how these changes impact
the interaction of tumor cells which hurts the immune system
and as a result, also on the clinical course of the disease
and on the response to immunotherapeutic strategies.
Now, today, I would like to discuss with you the changes which have been identified in
the expression and function of HLA class I antigen
processing machinery in malignant cells.
As you know, in human, unlike the animal species,
when cells undergo malignant transformation,
a number of changes occur,
and the changes involve the morphology,
the rate of proliferation,
and the expression of antigen,
just to mention a few.
Among the changed molecules are
the HLA class I antigens.
The reason why histocompatibility antigens
play such an important role is represented by the fact that
they are involved in the generation and presentation of
peptides from tumor antigens to the host immune system.
This function is played by
the antigen processing machinery which works in the following way.
In a very schematic and simple way,
the antigen processing machinery first cleaves tumor antigens,
and these are mostly endogenous proteins, into peptides,
which have the size of 9,11 amino acids long,
and which are transported by the transporter
associated with antigen processing to the endoplasmic reticulum.
In the endoplasmic reticulum,
the peptides are loaded on HLA class I antigens,
which are composed of a heavy chain non-covalently associated with the polypeptide,
which has been identified as Beta-2 microglobulin.
Now, the loading of the peptides on the dimer composed of HLA class I heavy chain
and Beta-2 microglobulin takes place with the help of several chaperone molecules,
whose function is to be sure that
the loading of the peptide on the HLA class I and
Beta-2 microglobulin dimer occurs in an optimal way since abnormalities
in these peptides may have
a negative impact on the presentation of the peptides to the immune system.
Now, once the peptide has been loaded on
the HLA class I heavy chain Beta-2 microglobulin complex,
the resulting trimolecular complex goes through the Golgi apparatus
and travels to the cell membrane where the presenting is done in the right way;
the peptide is presented to cognate CTL,
which will recognize the peptide,
will become activated, and will lyse the target cells.
It has been found that the complex of
antigen processing machinery may
undergo changes when cells undergo a malignant transformation.
These changes may be represented either by downregulation in the expression of
the components of the antigen processing machinery
or in the lack of expression of these components.
From a functional viewpoint,
that will result in an effective synthesis and
expression of the HLA class I to more antigen peptide complex.
Now, I'd like to first ask the question, well,
how do we identify the changes in the expression of
the HLA class I antigen processing machinery components in malignant cells?
This is done mainly by utilizing immunohistochemical staining of
tissue sections with antibodies which are specific for
the components of the antigen processing machinery.
The slide gives some examples of the staining of