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Tumor Immunology

This module will help you

• learn how tumors avoid the immune system
• see what anti-tumor immunotherapies are being developed.
• test your knowledge and immunology problem-solving skills.

Cancer cells are the progeny of a single transformed cell that undergo unregulated cell proliferation. Solid tumors are collections of attached cancer cells which can metastasize (spread) from their original site. "Liquid" tumors are leukocyte tumors that circulate in the blood and may also form masses elsewhere in the body. Cancer is thought to be the result of several sequential events, including genetic predisposition, transformation by viruses or environmental mutagens such as radiation and chemicals, and tumor promoters. The theory of immune surveillance says that the immune system continually recognizes and eliminates tumor cells; when a tumor escapes immune surveillance and grows too large for the immune system to kill, cancer is the result. Immune surveillance is most likely to be successful against virus-induced tumors which express foreign peptides. Tumors vary greatly in their immunogenicity, and even tumors with antigens which can be recognized by the host immune system can evade immune elimination.

Lack of tumor rejection by intact immune systems is not always due to the absence of antigens which can be recognized or to the absence of T cells which can recognize those antigens. Tumor-specific lymphocytes can be found in the blood, draining lymph nodes, and the tumor itself of patients with actively growing tumors. These lymphocytes can kill tumor cells in vitro but fail to do so in vivo. The presence of these cells has allowed immunologists to identify antigens on some tumor cells.

Some tumors have tumor-specific antigens (TSA, also called tumor-specific transplantation antigens, TSTA, or tumor rejection antigens, TRA) on their surface. TSA are not present on non-tumor cells. TSA usually appear when an infecting virus has caused the cell to become immortal and to express virus antigens. TSAs not induced by viruses are the idiotypes of BCR on B cell lymphomas or TCR on T cell lymphomas. Tumor-associated antigens (TAA) are more common. TAA are found on tumor cells and on normal cells during fetal life (onco-fetal antigens), after birth in selected organs, or in many cells but at much lower concentration than on tumor cells. Immune responses to TAA may be suppressed because they are considered "self". The table below illustrates some known tumor antigens.

Oncogenes were discovered in cancer-causing viruses. Most oncogenes were actually present in the host cell, where they functioned in regulated cell growth. The host cell gene was called a proto-oncogene. When transduced by the virus and expressed under the control of a viral promotor, the gene product contributes to the unregulated growth of the tumor cell. Since proteins encoded by proto-oncogenes are expressed by normal cells, their over-expression on tumor cells would qualify them as tumor-associated antigens.

If NK cells and tumor-specific CTL can be induced to kill tumor cells in vitro, why don't these responses occur in tumor-bearing mice? One difficulty may be intrinsic lack of immunogenicity. Tumor cells may present only self peptides or downregulate Class I MHC expression. Tumor cells often lack co-stimulatory molecules like B7 or adhesion molecules that are necessary for them to interact with CD8 T cells. Tumors also shed their tumor antigens or change their structure spontaneously (antigenic variation) to avoid immune system elimination. Antibodies to tumor surface antigens may promote tumor survival (enhancing antibodies) if they bind without being cytotoxic, hiding the tumor antigens from T cells and inducing the tumor to downregulate tumor antigen expression. Some tumors actively suppress the immune response by producing TGFb, a suppressive cytokine that inhibits cellular immunity. Some tumors, including myeloma and HTLV-1 T cell leukemia, also produce cytokines that stimulate their own proliferation.

Adapted from Janeway et al. Immunobiology (5th ed.). Garland Press,New York, 2001.

Tumors can be detected by using radioisotopically-labeled mouse monoclonal antibodies to tumor-specific and tumor-associated antigens. These antibodies are also useful for assessing the success of tumor therapy by testing for shrinkage of the tumor. Immunotherapy of tumors is usually not done until conventional therapies like surgery, chemotherapy and radiation have been tried for practical and ethical reasons. Debulking the tumor is essential for success of immunotherapy, but surgery, radiation and chemotherapy all suppress immune function.

Attempts have been made to use tumor-specific antibodies to kill tumor cells by linking the antibodies to toxins, anti-tumor drugs, or very energetic radioisotopes. Problems with these therapies include the necessity of making a unique antibody for each tumor, which is time-consuming and expensive, lack of antibody access to the tumor center, and production of a human-anti-mouse-antibody (HAMA) response to xenogeneic monoclonal antibodies. Production of human monoclonals has proved difficult, but chimeric antibodies and humanized antibodies can be made which are less immunogenic. Some mAb have been able to induce tumor remission or elimination in a few patients.

Adapted from Janeway et al. Immunobiology (5th ed.). Garland Press, New York, 2001.

Cytokines are used clinically to treat tumors. IL-2, IFNa, and TNFa are used in vivo, and IL-2 is used in vitro to expand populations of lymphokine-activated killer (LAK) cells and tumor-infiltrating lymphocytes (TILs) so they can be returned to the patient to kill tumor cells. Limitations on therapeutic use of cytokines include the need for locally high concentrations, their short biological half lives, and side effects such as vascular shock and psychoses. Introduction of irradiated tumor cells transfected with genes for cytokines that stimulate immunity or antisense genes for inhibitory cytokines are undergoing clinical trials. For example, a GM-CSF gene transfected into tumor cells recruits hematopoietic precursors and induces them to become dendritic cells which can take up and present tumor antigens to T cells.

Other immunotherapies in human trials include melanoma vaccines. These vaccines employ the patient's tumor cells (irradiated to prevent growth) along with adjuvant (BCG or Corynebacterium parvum). Melanoma vaccines have induced tumor remission in some patients. Whole protein, peptide, and recombinant vaccines are also being developed. Irradiated tumor cells transfected with B7 are being injected in the hopes that they can activate specific T cells. Heat Shock Proteins (HSP) from tumor cells are being tested as possible vaccines. HSP are peptide chaperones; their concentration increases in damaged cells from many species (including prokaryotes). It has been discovered that professional APC bind HSP and deliver their peptides to the Class I MHC presentation pathway. Finally, tumor antigen-pulsed autologous dendritic cells are being tested for their ability to stimulate a tumor-specific immune response.

Practice Quiz

Pick the one BEST answer for each question by clicking on the letter of the correct choice.

1. Cancer is caused by

a. chemicals.
b. radiation.
c. spontaneous mutations.
d. viruses.
e. all of the above.

2. Tumor-associated antigens CANNOT be

a. expressed on non-tumor cells.
b. onco-fetal antigens.
c. over-expressed self antigens.
d. presented on MHC Class I.
e. tumor-specific.

3. Tumors do NOT escape immune surveillance by

a. downregulating their expression of MHC Class I.
b. expressing antigens which are not found on other self tissues.
c. failing to express B7.
d. producing immunosuppressive cytokines like TGFb.
e. shedding their membrane antigens.

4. A virus molecule expressed on the membrane of a virus-induced tumor cell is an example of a(n)

a. angiogenic molecule.
b. carcinoembryonic antigen.
c. proto-oncogene.
d. tumor-associated antigen.
e. tumor-specific antigen.

5. Proto-oncogenes can be activated to become oncogenes and cause cancer by

a. carcinogens in cigarette smoke.
b. overexposure to UV radiation in sunlight.
c. spontaneous mutations.
d. virus infection.
e. all of the above.

6. Enhancing antibodies

a. enhance the ability of CTL to eliminate tumor cells.
b. enhance tumor growth by blocking access of CTL to tumor cells.
c. kill tumor cells when administered to the cancer patient.
d. promote APC uptake of tumor antigen via FcR.
e. promote tumor detection when used to generate a HAMA response.

7. Experimental approaches that may result in new immunotherapies for cancer include all of the following EXCEPT

a. monoclonal antibodies to tumor antigens coupled with cytotoxic drugs.
b. patient dendritic cells pulsed with tumor heat shock proteins.
c. vaccines containing live tumor cells to induce vigorous CTL responses.
d. vaccines containing tumor cells transfected with a gene for B7.
e. vaccines containing tumor cells transfected with an antisense gene for TGFb.

Problem

Melanomas are fast-growing skin tumors which metastasize to distant locations in the body. They express tumor-associated antigens MAGE-1 and MAGE-3, which are also found on testicular tissue. How could you use monoclonal antibodies to MAGE to kill metastatic cancer? Include a description of the side effects of this therapy and why it might not be successful.

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