TUMOR IMMUNITY

1.            Tumor-associated Antigens

a.         Animals carrying a chemically or virally induced malignant tumor can develop resistance to that tumor and cause its regression.

b.         In the course of neoplastic transformation, new antigens, called tumor rejection antigens (TRAs) develop at the cell surface and the host recognizes such cells as ‘nonself’.

c.         Some human tumors contain antigens that normally occur in fetal but not in adult human cells.

d.            Carcinoembryonic antigen:

i.            circulates at elevated levels in the serum of many patients with carcinoma of the colon, pancreas, breast or liver.

ii.          it is found in fetal gut, liver, and pancreas and in very small amounts in normal sera.

iii.         if the level declines after surgery, it suggests that the tumor is not spreading.

iv.            conversely a rise in its level in patients with resected carcinoma of the colon suggests recurrence or spread of the tumor.

e.         Alpha-fetoprotein:

i.          it is present at elevated levels in the sera of hepatoma patients and is used as a marker for this disease.

ii.          it is produced by fetal liver and is found in small amounts in some normal sera.

iii.         it is however, nonspecific; it occurs in several other malignant and nonmalignant diseases.

f.          Origin of TRAs:

i.          TRAs are peptides of cellular proteins presented by self MHC class I molecules.

ii.          in some cases, proteins that are normally expressed only in embryonic tissues are re-expressed by the tumor cells.

iii.         as these proteins are normally expressed at a time when the immune system is not developed, T cells are not tolerant of these self antigens and can respond to them as if they were foreign proteins.

iv.         in other tumors, over-expression of a self protein increases the density of presentation of a normal self peptide on tumor cells.

v.         such peptides are then presented at high enough levels to be recognized by T cells.

2.            Mechanisms of Tumor Immunity

a.         Cell-mediated reactions attack these ‘nonself’ tumor cells and limit their proliferation.

b.         Such immune responses probably act as a surveillance system to detect and eliminate newly arising clones of neoplastic cells.

c.         In general, the immune response against tumor cells is weak and can be overcome experimentally by a large dose of tumor cells.

d.         The cell-mediated immune responses that affect tumor cells are:

i.          natural killer cells, which act without antibody.

ii.          killer cells, which mediate antibody-dependent cytolysis.

iii.            cytotoxic T cells.

iv.            activated macrophages.

3.         Escape Mechanisms of Tumors

a.         Low Immunogenicity:

i.          some tumors do not have peptides of novel proteins that can be presented by MHC molecules, and therefore appear normal to the immune system.

ii.          others have lost one or more MHC molecules, and most do not express co-stimulatory proteins, which are require to activate naive T cells.

b.            Antigenic modulation:

i.          tumors may initially express antigens to which the immune system responds but lose them due to antibody-induced internalization or antigenic variation.

ii.          when tumors are attacked by cells responding to a particular antigen, any tumor that does not express that antigen will have a selective advantage.

iii.         some antibodies, called blocking antibodies, enhance tumor growth by blocking recognition of tumor antigens by the host.

c.         Tumors produce substances such as TGF-b, that suppress immune responses directly.

4.         Cancer Immunotherapy

a.            Monoclonal antibodies:

i.            monoclonal antibodies directed against new surface antigens on malignant cells can be useful in both diagnosis and therapy.

ii.            monoclonal antibodies coupled to a gamma-emitting isotope such as Technetium have also been used to image tumors, for the purpose of diagnosis and monitoring of metastatic disease.

iii.         the first reported successful treatment of a tumor with monoclonal antibodies utilized anti-idiotypic antibodies to target B-cell lymphomas whose surface immunoglobulin expressed the specific idiotype.

iv.            monoclonal antibodies coupled to toxins such as Pseudomonas toxin may enhance its killing ability.

b.            Enhancing Immune responses:

i.            spontaneously arising human tumors may have new cell surface antigens against which the host develops both cytotoxic antibodies and cell-mediated immune responses.

ii.            enhancement of these responses can contain the growth of some tumors.

iii.         for example, the administration of the BCG vaccine (bacillus Calmetta-Guerin, a bovine mycobacterium) into surface melanomas can lead to their partial regression.

c.            Enhancing of Immunogenicity of tumors:

i.          a tumor that does not express co-stimulator molecules will not induce an immune response, even though it may express tumor rejection antigens, because naive CD8 T cells specific for TRA cannot be activated by the tumor.

ii.          the immunogenicity of tumor cells can be increased by introducing genes that encode co-stimulatory molecules or cytokines into the tumor cells.

iii.         if such tumor cells are transfected with a co-stimulator molecule, such as B7, TRA-specific cells can now be activated.

d.            Modulation of cytokine release:

i.            cytokine genes are introduced into tumors so that they secrete the relevant cytokine aimed at attracting antigen-presenting cells to the tumor.

ii.          for example, tumor cells that secrete GM-CSF attracts haematopoietic precursors to the site and induces their differentiation into dendritic cells.