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Chapter 24 : Cancer and the Immune System

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Abstract:

Immunological control of cancers could conceivably play a role in the eradication of primary tumors and disseminated metastases as well as the residual cancer cells that remain after conventional treatment regimens. The ideal result of immunotherapy would be the specific eradication of cancer cells with minimal damage to normal host cells. Attainment of the goal of effective immunotherapy for tumors requires an understanding of how the immune system both fails to respond to cancer cells and has the potential to respond and the ways in which this response can be strategically manipulated. Early experimental studies of the immune response to tumors focused on the outgrowth versus rejection of tumor fragments transplanted between outbred mice. Tumor rejection in these cases was thought to reveal the existence of tumor-specific antigens and suggested that the immune system could be used to control cancer. The tumor surveillance theory states that mammalian cells undergo transformation to cancerous or precancerous states very frequently, but that the immune system successfully recognizes and destroys these transformed cells in most cases. Individuals with Chediak-Higashi syndrome (CHS) are at an increased risk for some types of cancer, as predicted by the tumor surveillance theory. The first generation of tumor-specific vaccines was relatively crude and consisted of whole cancer cells that were either irradiated or lysed.

Citation: Butterfield L, Schoenberger S, Lyczak J. 2004. Cancer and the Immune System, p 573-592. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch24

Key Concept Ranking

Major Histocompatibility Complex
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Tumor Necrosis Factor alpha
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Figures

Image of Figure 24.1
Figure 24.1

Cancer deaths in the United States, comparing the period from 1950 to 1969 with the period from 1970 to 1994. Data are for white males of all ages, are grouped according to county, and are expressed as the number of cancer-related deaths per 100,000 person-years. The vertical black bar in the center of each graph shows the nationwide average of cancer-related deaths. Data are from the National Cancer Institute's Atlas of Cancer Mortality, which can be viewed at http://www3.cancer.gov/atlasplus/.

Citation: Butterfield L, Schoenberger S, Lyczak J. 2004. Cancer and the Immune System, p 573-592. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch24
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Image of Figure 24.2
Figure 24.2

Schematic diagram of a typical eukaryotic cell showing the factors or conditions that regulate its growth. Exogenous factors, stimuli, or cues are shown in black type. Growth inhibitory factors and events are shown with red arrows. Growth stimulatory factors and events are shown with green arrows. TNF-R, tumor necrosis factor receptor; CAM, cell adhesion molecule; FAK, focal adhesion kinase; RB, retinoblastoma tumor suppressor protein; TF, transcription factor.

Citation: Butterfield L, Schoenberger S, Lyczak J. 2004. Cancer and the Immune System, p 573-592. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch24
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Figure 24.3

The multistep process of tumorigenesis. The cell, which is originally normal (at the left), undergoes several genetic changes in a stepwise fashion. Each genetic change results in a phenotypic alteration that favors unregulated growth, exemption from apoptotic signals, genetic instability, and metastasis (ability to spread from its original tissue site to other remote tissues of the host).

Citation: Butterfield L, Schoenberger S, Lyczak J. 2004. Cancer and the Immune System, p 573-592. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch24
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Image of Figure 24.4
Figure 24.4

Conversion of a normal proto-oncogene to a cancer-promoting oncogene can result from changes in expression of the proto-oncogene or from alterations in the activity of the protein encoded by the protooncogene. The proto-oncogene encodes a protein tyrosine kinase. Point mutation at the 39 end of the gene results in loss of the tyrosine at position 527 (Tyr) that is crucial for negative regulation of the kinase's enzymatic activity. The regulatory tyrosine also can be lost by insertion of viral DNA that interrupts the gene coding sequence prior to Tyr. In either case, the mutant form of the kinase is constitutively active. The proto-oncogene encodes a transcription factor that helps regulate cell division and cell death. Chromosomal translocation between the q arm of chromosome 8 and the q arm of chromosome 14 places the gene in the middle of the Ig heavy chain locus, enhancing transcription of the gene in B cells. This results in dysregulated cell division and the formation of B lymphomas. Insertion of the human T-lymphotropic virus type 1 (HTLV-1) provirus near the proto-oncogene causes overexpression of , driven by strong enhancer elements in the viral long terminal repeats (LTRs). The virus encodes a protein called Tax that activates several host cell transcription factors (TF). The activated TFs then enhance transcription from the nearby promoter (P[yellow oval]) by binding to the proviral LTR.

Citation: Butterfield L, Schoenberger S, Lyczak J. 2004. Cancer and the Immune System, p 573-592. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch24
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Figure 24.5

Solid tumors induce angiogenesis and direct new blood vessels to grow into the tumor, providing the tumor with nutrients and waste removal. Growing tumor masses stimulate angiogenesis by causing local tissue injury thus activating the thrombin cascade Thrombin activates endothelial cells and platelets to produce matrix metalloproteases (MMPs), VEGF, and tissue factor (TF). VEGF directs growth and elongation of vascular endothelium MMPs dissolve extracellular matrix (ECM) components to allow growth of new vascular endothelium TF stimulates further production of thrombin, setting up a positive feedback loop Some tumors secrete VEGF to enhance this process Reprinted from D. E. Richard et al., 1556–1562, 2001, with permission.

Citation: Butterfield L, Schoenberger S, Lyczak J. 2004. Cancer and the Immune System, p 573-592. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch24
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Figure 24.6

Use of inbred mouse strains to demonstrate antigen-specific immune protection against transplanted tumors. A tumor transplanted from one mouse to another will usually grow in the recipient mouse if the donor and recipient mice are of the same strain, since the tumor will appear as self tissue to the immune system of the recipient. However, the transplanted tumor will always be rejected by the immune system of the recipient mouse if the donor and recipient are of different strains. Chemically induced tumors sometimes express antigens that are the result of mutagenesis and are unique to each tumor (TSAs). Killing tumor X from mouse 1 allows it to be used as a vaccine. If tumor X expresses a TSA, then a mouse vaccinated against tumor X will subsequently be protected against challenge with live cells from tumor X. This protection is antigen specific, since the vaccinated mouse is not protected from challenge with live cells from tumor Y.

Citation: Butterfield L, Schoenberger S, Lyczak J. 2004. Cancer and the Immune System, p 573-592. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch24
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Image of Figure 24.7
Figure 24.7

Genetic approach to identifying TSAs. Tumor cells are isolated from a tumor-bearing mouse and are used to prepare a tumor cell cDNA library. This library is then cloned into a cell line. Any cell that receives cDNA encoding a TSA (red squiggle) will express that TSA. TSA-expressing cells can be identified as being susceptible to killing by CTLs isolated from a vaccinated mouse that is resistant to tumor growth.

Citation: Butterfield L, Schoenberger S, Lyczak J. 2004. Cancer and the Immune System, p 573-592. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch24
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Image of Figure 24.8
Figure 24.8

Method for SEREX detection of tumor antigens. A cDNA library is prepared from a human tumor and is used to transfect bacteria. These bacteria are then lysed on a filter, and the filter is then probed with the serum of the same patient from which the tumor was taken. A bacterial clone that is positively detected by the patient's serum contains tumor cDNA encoding a TSA. Adapted from O. Tureci et al., 342–349, 1999.

Citation: Butterfield L, Schoenberger S, Lyczak J. 2004. Cancer and the Immune System, p 573-592. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch24
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Image of Figure 24.9
Figure 24.9

Emergence of tumor variants that escape T-cell-mediated cytotoxicity. Tumor cells can evade recognition or killing if they reduce their expression of TSAs reduce their expression of MHC class I or stop expressing CD95L that initiates the apoptosis pathway upon CTL recognition Last, tumor cells can escape cytotoxicity by overexpression of the antiapoptotic protein Bcl-2

Citation: Butterfield L, Schoenberger S, Lyczak J. 2004. Cancer and the Immune System, p 573-592. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch24
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Image of Figure 24.10
Figure 24.10

Tumor cells can be genetically engineered to make them more effective at CTL activation. The original tumor cell may express a TSA, but with low or no expression of costimulatory activity; CTLs that recognize the tumor cell are not efficiently activated and may even be anergized. If the tumor cell is transfected with the gene for IL-2 or B7 , then the engineered tumor cell can effectively activate tumor-specific CTLs. Alternatively, the tumor cell can be engineered to express cytokines that recruit and activate professional antigen-presenting cells, for example, IFN-γ (). The IFN-γ binds to a receptor on a macrophage (), activating the macrophage and making it more effective at capturing and presenting () tumor antigens to helper T cells. The activated helper T cells secrete other cytokines such as IL-2 () that then help stimulate tumor-specific CTLs ().

Citation: Butterfield L, Schoenberger S, Lyczak J. 2004. Cancer and the Immune System, p 573-592. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch24
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Image of Figure 24.11
Figure 24.11

Loss of TSAs during an immune response is attributable to a stochastic variability of TSA expression and selection against those tumor cells that express higher amounts of the TSA.

Citation: Butterfield L, Schoenberger S, Lyczak J. 2004. Cancer and the Immune System, p 573-592. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch24
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Image of Figure 24.12
Figure 24.12

Production of bispecific heteroconjugate antibodies as antitumor reagents. If MAbs specific for a tumor and for the CTL antigen CD3 are synthesized in the same cell, the resulting heteroconjugate is specific for both cell types, and can help CTLs attach to tumor cell targets. One drawback of this approach is that some of the antibodies are assembled into hybrid antibodies that recognize neither antigen. One solution to this problem is to purify both MAbs and then chemically conjugate them

Citation: Butterfield L, Schoenberger S, Lyczak J. 2004. Cancer and the Immune System, p 573-592. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch24
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Image of Figure 24.13
Figure 24.13

Immunotoxins are derived from MAbs and bacterial toxins. Diagram of two prototypical two-subunit toxins, diphtheria toxin and Shiga toxin. Both have active (A) subunits that contain their enzymatic activity as well as binding (B) subunits that allow the toxin to specifically associate with, and enter, its target cell. () Mode of action of Shiga toxin. Shiga toxin enters cells by recruiting clathrin on the membrane of its target cell to form coated pits. The toxin is then trafficked through the Golgi apparatus and endoplasmic reticulum (ER). During this transport, the toxin is cleaved by the enzyme furin to liberate the A subunit. The A subunit translocates to the cytoplasm where it cleaves the 59-terminal adenine from the 28S rRNA, preventing its assembly with the 60S ribosomal subunit. In an immunotoxin, the B subunit of the bacterial toxin is removed and replaced with a monoclonal antibody recognizing a tumor antigen. In the example shown, the A subunit of Shiga toxin is fused to the heavy chain of an antitumor antibody.

Citation: Butterfield L, Schoenberger S, Lyczak J. 2004. Cancer and the Immune System, p 573-592. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch24
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References

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1. Foss, F. M. 2002. Immunologic mechanisms of antitumor activity. Semin. Oncol. 29(3 Suppl. 7):511.
2. Hanahan, D.,, and R. A. Weinberg. 2000. The hallmarks of cancer. Cell 100:5770.
3. Helder, M.N.,, G. B. Wisman,, and G. J. van der Zee. 2002. Telomerase and telomeres: from basic biology to cancer treatment. Cancer Investig. 20:82101.
4. Homey, B.,, A. Muller,, and A. Zlotnik. 2002. Chemokines: agents for the immunotherapy of cancer? Nat. Rev. Immunol. 2:175184.
5. Knudson, A. G. 2001. Two genetic hits (more or less) to cancer. Nat. Rev. Cancer 1:157162.
6. Moingen, P. 2001. Cancer vaccines. Vaccine 19:13051326.
7. Perez-Diez, A.,, and F. M. Marincola. 2002. Immunotherapy against antigenic tumors: a game with a lot of players. Cell Mol. Life Sci. 59:230240.
8. Reff, M. E.,, K. Hariharan,, and G. Braslawsky. 2002. Future of monoclonal antibodies in the treatment of hematologic malignancies. Cancer Control 9:152166.
9. Ribas, A.,, L. H. Butterfield,, J. A. Glaspy,, and J. S. Economou. 2002. Cancer immunotherapy using gene-modified dendritic cells. Curr. Gene Ther. 2:5778.
10. Rosenberg, S. A. 2001. Progress in the development of immunotherapy for the treatment of patients with cancer. J. Intern. Med. 250:462475.
11. Tindle, R. W. 2002. Immune evasion in human papillomavirus-associated cervical cancer Nat. Rev. Cancer 2:5965.
12. Wang, S. C.,, L. Zhang,, G. N. Hortobagyi,, and M. C. Hung. 2001. Targeting HER2: recent developments and future directions for breast cancer patients. Semin. Oncol. 28:2129.

Tables

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Table 24.1

Nomenclature of several types of cancer

Citation: Butterfield L, Schoenberger S, Lyczak J. 2004. Cancer and the Immune System, p 573-592. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch24
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Table 24.2

Biochemical basis for stimulation of cell growth by oncogenes

Citation: Butterfield L, Schoenberger S, Lyczak J. 2004. Cancer and the Immune System, p 573-592. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch24
Generic image for table
Table 24.3

Characteristics acquired during emergence of a tumor cell

Citation: Butterfield L, Schoenberger S, Lyczak J. 2004. Cancer and the Immune System, p 573-592. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch24
Generic image for table
Table 24.4

Comparison of TSAs and TAAs

Citation: Butterfield L, Schoenberger S, Lyczak J. 2004. Cancer and the Immune System, p 573-592. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch24
Generic image for table
Table 24.5

Examples of TSAs

Citation: Butterfield L, Schoenberger S, Lyczak J. 2004. Cancer and the Immune System, p 573-592. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch24

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