Page 245 - Textbook of Pathology, 6th Edition

of malignant melanoma temporarily from the primary site normal adult tissues except in male germ line but MAGE 229
which may then reappear as metastasis. genes are expressed on surface of many tumours such as
3. It is highly unusual to have primary and secondary melanoma (abbreviation MAGE from ‘melanoma antigen’ in
tumours in the spleen due to its ability to destroy the growth which it was first found), cancers of liver, lung, stomach and
and proliferation of tumour cells. oesophagus. Other examples of similar aberrantly expressed
4. Immune surveillance exists is substantiated by increased gene products in cancers are GAGE (G antigen), BAGE (B
frequency of cancers in immunodeficient host e.g. in AIDS melanoma antigen) and RAGE (renal tumour antigen). CHAPTER 8
patients, or development of post-transplant lymphoprolife- 5. Tumour antigens from viral oncoproteins. As already
rative disease. discussed above, many oncogenic viruses express viral
In an attempt to substantiate the above observations and oncoproteins which result in expression of antigens on
to understand the underlying host defense mechanisms, tumour cells e.g. viral oncoproteins of HPV (E6, E7) in cervical
experimental animal studies involving tumour transplants cancer and EBNA proteins of EBV in Burkitt’s lymphoma.
were carried out. The findings of animal experiments coupled 6. Tumour antigens from randomly mutated genes. Various other
with research on human cancers has led to the concept of carcinogens such as chemicals and radiation induce random Neoplasia
immunology of cancer discussed under the following mutations in the target cells. These mutated cells elaborate
headings: protein products targeted by the CTL of the immune system
1. Tumour antigens causing expression of tumour antigens.
2. Antitumour immune responses 7. Cell specific differentiation antigens. Normally differentiated
3 Immunotherapy. cells have cellular antigens which forms the basis of
diagnostic immunohistochemistry. Cancers have varying
1. TUMOUR ANTIGENS. Tumour cells express surface degree of loss of differentiation but particular lineage of the
antigens which have been seen in animals and in some tumour cells can be identified by tumour antigens. For
human tumours. Older classification of tumour antigens was example, various CD markers for various subtypes of
based on their surface sharing characteristics on normal lymphomas, prostate specific antigen (PSA) in carcinoma of
versus tumour cells and on their recognition by cytotoxic T prostate.
lymphocytes CTL (CD8+T cells) on the basis of class I MHC 8. Oncofoetal antigens. Oncofoetal antigens such as α-
molecules. Accordingly, tumour antigens were categorised foetoprotein (AFP) and carcinoembryonic antigen (CEA) are
into following two types: normally expressed in embryonic life. But these antigens
i) Tumour-specific antigens (TSAs) located on tumour cells appear in certain cancers—AFP in liver cancer and CEA in
and are unique or specific antigens for particular tumour and colon cancer which can be detected in serum as cancer
not shared by normal cells. markers.
ii) Tumour associated antigens (TAAs) are present on tumour 9. Abnormal cell surface molecules. The normal cell expresses
cells as well as on some normal cells from where the tumour surface molecules of glycolipids, glycoproteins, mucins and
originated. blood group antigens. In some cancers, there is abnormally
However, it is now known that TSAs and TAAs can both
be present on normal cells and categorisation into TSA and changed expression of these molecules. For example, there
may be changed blood group antigen, or abnormal
TAA does not hold true. Thus, presently distinction of expression of mucin in ovarian cancer (CA-125) and in breast
tumour antigens is based on their recognition by the host cancer (MUC-1).
immune cells, i.e. CD8+ T cells (CTL), and by the molecular
structure of the tumour antigens. Currently, various groups 2. ANTI-TUMOUR IMMUNE RESPONSES. Although the
of tumour antigens are as follows: host immune response to tumour is by both cell-mediated
1. Oncoproteins from mutated oncogenes: Protein products and humoral immunity, the major anti-tumour effector
derived from mutated oncogenes result in expression of cell mechanism is cell-mediated.
surface antigens on tumour cells. The examples include i) Cell-mediated mechanism. This is the main mechanism
products of RAS, BCL/ABL and CDK4. of destruction of tumour cells by the host. The following
2. Protein products of tumour suppressor genes. In some tumours, cellular responses can destroy the tumour cells and induce
protein products of mutated tumour suppressor genes cause tumour immunity in humans:
expression of tumour antigens on the cell surface. The a) Specifically sensitised cytotoxic T lymphocytes (CTL) i.e.
examples are mutated proteins p53 and β-catenin. CD8+ T cells are directly cytotoxic to the target cell and
3. Overexpressed cellular proteins. Some tumours are associated require contact between them and tumour cells. CTL have
with a normal cellular protein but is excessively expressed been found to be effective against virally-induced cancers
in tumour cells and incite host immune response. For e.g. in Burkitt’s lymphoma (EBV-induced), invasive
example, in melanoma the tumour antigen is structurally squamous cell carcinoma of cervix (HPV-induced).
normal melanocyte specific protein, tyrosinase, which is b) Natural killer (NK) cells are lymphocytes which after
overexpressed compared with normal cells. Similarly, HER2/ activation by IL-2, destroy tumour cells without sensitisation,
neu protein is overexpressed in many cases of breast cancer. either directly or by antibody-dependent cellular cytotoxicity
4. Abnormally expressed cellular proteins. Sometimes, a cellular (ADCC). NK cells together with T lymphocytes are the first
protein is present in some normal cells but is abnormally line of defense against tumour cells and can lyse tumour cells.
expressed on the surface of tumour cells of some cancers. c) Macrophages are activated by interferon-γ secreted by
The classic example is presence of MAGE gene silent in T-cells and NK-cells, and therefore there is close collaboration