Chapter 34 | Adaptive Immune System | Immune System

Chapter 34: Tumor Immunology

 LYMPHOID TUMORS:
 The malignancies affecting the adaptive immune system originate from a single lymphocyte or plasma cell; which has undergone identical immune receptor gene rearrangements and expresses identical immunoglobulin or T-cell receptor molecules; referred to as monoclonality.  The characteristics of each type of tumor are determined by the biology of the originating cell.  E.g. ALL is derived from rapidly dividing pre-B cells and is extremely aggressive. Untreated ALL can kill within weeks of diagnosis.

 Myeloma is derived from mature, slow-growing plasma cells, which secrete monoclonal
immunoglobulin. Myeloma patients can survive for years without treatment.

Oncogenesis Chromosomal Translocations  It occurs due to failure of repairing of the chromosomal breaks which occurs in: 1. During immune-receptor gene recombination 2. During class switching.  Most of the time; chromosomal translocations are lethal; however, some rare chromosomal translocations have positive effects on cell survival. Example  In lymphoma, the oncogenes c-myc (chromosome 8) and bcl-2 (chromosome 18) are commonly translocated to the immunoglobulin heavy chain gene on chromosome 14  Activated c-myc stimulates lymphocyte proliferation  activated Bcl-2 protein protects against apoptosis, and this allows unrestrained proliferation of lymphocytes.  Oncogene translocations are more likely to occur after exposure to radiation [Myeloma was common in survivors of the Hiroshima atomic bombings].

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Pathogens  Herpesvirus family members and retroviruses stimulate uncontrolled growth of these infected cells.  Epstein-Barr virus (EBV) causes infectious mononucleosis/glandular fever, lymphoma, and nasopharyngeal carcinoma.  EBV does not convert the cellular machinery to virus production and destruction of the cell, but it immortalizes cells by producing proteins that drive B-cell proliferation and inhibit apoptosis.

 EBV proteins also help infected cells to evade the immune response by blocking proteosomemediated antigen degradation.

 EBV causes lymphoma, particularly in two situations. 1. In regions where malaria is endemic, Burkitt's lymphoma occurs in up to 1 in 1000
children. Burkitt's lymphoma is a consequence of polyclonal activation of B cells by both malaria and EBV. The polyclonal B-cell proliferation increases the risk for translocations involving myc, leading to the growth of a malignant population.

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In immunodeficient patients.

 Infection with another herpes virus, human herpes virus 8 (HHV8), can cause Kaposi's sarcoma in immunodeficient individuals.  Helicobacter pylori can contribute to the development of lymphoma.  It triggers chronic inflammation in the stomach  causes stomach ulcers  rarely, causes lymphomas to arise in the associated mucosa-associated lymphoid tissue.

 Treatment of the H. pylori infection can lead to remission of lymphoma.
 T-cell malignancy is often caused by human T lymphotrophic virus 1 (HTLV1).  It is a retrovirus that encodes Tax protein, which has effects that are similar to IL-2. It is rare in the developed world.  Cancers are a consequence of at least two events affecting gene expression. Diagnosing Lymphoid Malignancy 1. Abnormal appearance.  Acute leukemia; the presence of high numbers of ("blasts") in the blood and marrow.

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 Flow cytometry may then be used to distinguish between acute myeloid leukemia (AML) arising
from neutrophil precursors and acute lymphoblastic leukemia (ALL) arising from immature B-cell precursors.  In some situations, the malignant cells look very similar to their normal counterparts.  For example, in (CLL), the abnormal cells look very similar to normal, mature lymphocytes. Flow cytometry can be used to show the presence of abnormal molecules on the surface of the leukemia cells.  (Myeloma) is a special case. The monoclonal immunoglobulin secreted by these cells acts as a marker of malignancy.

 IMMUNITY TO TUMORS:
 Components of the immune system may recognize and, sometimes, kill malignancies arising in other tissues. Tumor Antigens  Tumor antigens are molecules produced by tumor cells that can be recognized by the immune system. There are a number of different types of tumor antigen: 1. Developmental proteins.  These are normally only transiently expressed during development but may be reexpressed by tumor cells.  For example, carcinoembryonic antigen is normally expressed on many tissues during fetal life; but can be abnormally expressed in gastrointestinal cancer. Lineage-specific proteins.  These proteins are expressed in cancers and the normal tissues from which they arise.  For example, normal melanocytes and melanoma cells both express the enzyme tyrosinase. Tyrosinase is not expressed in any other cells, normal or abnormal. Viral proteins.  For example, EBV and human papilloma virus (in cervical cancer) produce specific proteins. Proteins produced through translocations.  For example, the Bcr-Abl fusion protein is the product of the bcr/abl translocation.

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 Developmental and lineage-specific proteins are poorly immunogenic because they are expressed on
normal tissues.  T cells with receptors capable of recognizing these proteins are deleted through tolerance induction; and the same system that protects from autoimmunity thus impairs tumor recognition by the immune system.

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 Viral and fusion proteins tend to be more immunogenic because they are never present in the normal
individual.

 The greatest victory so far in preventing tumors is an indirect one.  In some parts of the world, the risk for hepatoma caused by hepatitis B virus has been dramatically reduced following the introduction of hepatitis B vaccine. Evidence for Tumor Immunity  The high frequency of cancers in immunosuppressed patients is an evidence for tumor immunity, for example: 1. Papilloma virus-driven cervical cancer (which is 100 times more common in immunosuppressed patients). 2. EBV-driven lymphoma is in patients with immunodeficiency.  The high prevalence of these tumors in immunodeficient patients is evidence of the more effective role of the immune system in clearing viral infection than in recognizing tumors themselves. (Immune surveillance for viruses is much more effective than surveillance for cancers).

 Most research has focused on T cells (e.g., tumorinfiltrating lymphocytes [TIL]) that are specific for tumor antigens (e.g., tyrosinase in melanoma). TILs use their T-cell receptors to recognize antigen presented by MHC.  Occasionally, the immune system damages the blood supply to tumors and kills them by starving them of oxygen, leading to necrosis.

 Experiments showed that (TNF) can do this when
injected at high doses into mice with cancers, but it is not clear how important any of these mechanisms are in tumors in humans. Evasion of the Immune Response By Tumors  Tumors very rarely produce danger signals and do not directly activate the innate immune system; so apart from natural-killer cells, this means that the innate immune system does not usually attempt to kill tumor cells or alert the adaptive immune response to the presence of danger.  Some tumors evade the adaptive immune system by decreasing expression of MHC and losing the ability to present antigen to T cells. Mutations in the MHC genes are usual finding in these tumors.  Cells expressing low levels of MHC make excellent targets for killing by natural-killer cells, which may act as a back-up system in this situation. 4/6

Immunotherapy  Although most tumor-immunity research has focused on T cells, two of the most successful drugs developed to date are monoclonal antibodies. 1. Passive Cancer Immunotherapy  Passive cancer immunotherapy depends on the use of monoclonal antibodies to destroy malignant cells; and two different sets of monoclonal antibody have achieved widespread use for cancer immunotherapy. 1. Anti-CD20 ( a monoclonal antibody).

 CD20 is expressed on normal B cells and on lymphoma cells.  Infusion of anti-CD20 can reduce or cure up to 50% of B-cell lymphomas.  It destroys malignant B cells by activating antibody-dependent complement and cellmediated cytotoxicity. It also triggers B-cell signaling, which induces apoptosis.

 Anti-CD20 molecules have been conjugated to radioiodine to deliver high doses of
radioactivity directly to the site of the tumor.

 Antibodies such as CD20 against normal antigens will damage normal cells.  Radiolabeled anti-CD20 can also be used to determine the spread of lymphoma in the
body. 2. Trastuzumab (Herceptin™) is a humanized monoclonal antibody that is specific for HER-2.

 HER-2 is the human epidermal growth factor receptor 2 and is essential for initiating and
maintaining tumor growth and progression in about 30% of breast cancers.

 Trastuzumab binds to and inactivates the HER-2 molecule, thus inhibiting tumor cell
growth. It also activates antibody-dependent cellular cytotoxicity by natural-killer cells and macrophages.

 These combined mechanisms are very effective in patients whose tumors express the HER2 receptor.

 In these cases, trastuzumab can induce remission in up to 30% of patients who have
already relapsed on conventional chemotherapy. 2. Active Cancer Immunotherapy

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 Active immunotherapy aims to overcome the anergy of T cells, which could develop if a tumor cell presents antigen to a T-helper cell without the necessary costimulatory molecules Way for providing costimulatory signals: 1. Toll-like receptor ligands.  CpG motifs bind to TLR9, and imiquimod binds TLR7. These drugs provide a danger signal for the innate immune system, which subsequently activates the adaptive immune system. 2. Infuse the patient with cytokines.  IL-2 treatment activates T cells (and natural-killer cells) directly; but unfortunately, IL-2 is pleiotropic and has many different effects on the immune system.

 High-dose IL-2 causes severe side effects (e.g. capillary leak syndrome, in which fluid shifts to
the extravascular space, causing edema and hypotension).  Systemic use of interferon IFN (both IFN-α and IFN-β): 1. Increases MHC class I expression, enabling improved tumor antigen presentation. 2. Have direct antiproliferative effects on tumor cells.
BOX: Myeloma

Tests used to diagnose Multiple Myeloma are: 1. Electrophoresis: Monoclonal band; which represent IgGk in the serum. 2. Urine analysis which shows Bence Jones protein; that represent free k light chin in urine. 3. Skull X-ray: It shows lytic bone lesions. 4. Bone marrow aspirate: shows high numbers of plasma cells in the bone marrow.  Monoclonal immunoglobulins can be produced in response to some infections, and they are seen in some healthy elderly people: so-called monoclonal gammopathy of uncertain significance (MGUS).  However, monoclonal immunoglobulin is also produced by malignant plasma cells in myeloma, in which case the number of marrow plasma cells is dramatically increased.  Bone destruction (osteolytic lesions) is seen in some patients with myeloma but never in MGUS, which helps to distinguish the two conditions.

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