Topic  22 Cancer and the Immune System

Introduction

Occasionally, a cell becomes altered in such a way that it grows uncontrollably and gives rise to a tumor.  Some of these cancerous cells may be sufficiently abnormal that they can trigger an immune response.  Sometimes that immune response can destroy the tumor.  In this section, we describe that immune response to cancer cells as well as the methods by which cancers manage to evade those responses.  The existence of an immune response against a tumor is based on changes in the surface components of the malignant cell that do not occur in its normal counterparts, and that give rise to structures that are antigenic.  Early researchers noticed that tumors transplanted from one animal to another were destroyed, usually after a short period of growth in the host.  When identical tumor cells were reinjected into the original animal again, they did not produce nodules or grow.   These findings were interpreted to mean that the animal that rejected the tumor did so because they had become immunologically resistant or immune to the tumor.  Subsequently, tumor-specific transplantation antigens (TSTAs), which have the ability to induce anti-tumor immune responses, have been demonstrated for many tumors in a variety of animal species, including humans.  Such tumor antigens, expressed in the neoplastic but not in the normal tissue, might exist after all and might even provide a means of destroying the tumor via an immune response.  Riding mainly on these hopes a whole sub-discipline of immunology developed - tumor immunology- the study of the immune response to tumors.  In this section we will also explore current clinical and experimental immunotherapies for cancer.

Objectives

On completion of this section and the required reading, you should be able to:

n  differentiate between a benign tumor and a malignant tumor;

n  describe the concept of immunosurveillance;

n  describe the different ways that tumors can camouflage themselves to evade immune defenses;

n  discuss the advantages of immunotherapy over other forms of cancer therapy;

n  distinguish between specific and nonspecific immunotherapy with the use of specific examples;

n  describe immunotoxins;

n  describe the development of humanized antibodies to tumor antigens;

n  evaluate the contribution of T cells, NK cells, Macrophages, and B cells to tumor immunity;

n  distinguish between tumor specific transplantation antigens and tumor associated transplantation antigens;

n  describe oncofetal antigens.

Required Reading

Please refer to the Textbook Key for the appropriate readings for this section.

 

P Key Words

•    antibody dependent cell mediated cytotoxicity (ADCC)

•    benign tumor

•    cancer

•    carcinogens

•    proto oncogens

•    immune surveillance

•    Specific immunotherapy

•    non specific immunotherapy

•    immunotoxins

•    Lymphokine activated killer cell (LAK)

•    malignancy

•    metastasis

•    malignant tumor

•    natural killer cells (NK)

•    neoplasm

•    oncofetal antigens

•    oncogens

•    tumor

•    tumor associated

•    antigens

•    tumor associated transplantation antigens

P Key Concepts

n  Tumor immunology deals with: the immunological aspects of the host-tumor relationship, and the utilization of the immune response for diagnosis, prophylaxis, and treatment of cancer.

n  When cells become neoplastic, they may gain new antigens and provoke an immune response.  This immune response may destroy the cancer cells.

n  Tumor antigens are typically weakly antigenic and do not stimulate a strong immune response.

n  In the immune response to tumors, both humoral and cellular immune responses and their effector mechanisms are expressed.  Destruction of tumor cells may be achieved by:

n   antibodies and complement, phagocytes,

n   loss of the adhesive properties of tumor cells caused by antibodies,

n   cytotoxic T lymphocytes,

n   antibody-dependent, cell mediated cytotoxicity

n   activated macrophages, NK cells, and LAK cells

n  Immunodiagnosis may be directed toward the detection of tumor antigens or the host’s immune response to the tumor.

n  Immunoprophylaxis may be directed against oncogenic viruses or against the tumor itself.

n  Immunotherapy of malignancy employs various preparations for the augmentation of tumor-specific as well as nonspecific immune responses. 

DID YOU KNOW?

LAK Therapy

If NK cells or NK-like (CD4-8-) T cells are incubated in the presence of IL-2 for four days, they develop cytotoxic properties and are called lymphokine-activated killer cells.  Injection of these LAK cells into mice with experimental lung tumors can lead to cancer remission.  A combination of LAK cells and IL-2 has given encouraging results when administered to humans with cancer:

To receive lymphokine-activated killer cell (LAK) therapy, the patient is first given interleukin-2 for five days.  This IL-2 causes a significant leukocytosis.  After waiting for 24 hours after the last dose, the patient is bled daily and blood subjected to leukophoresis for one week.  (The leukocytes are removed and the erythrocytes returned to the patients.)  These leukocytes are incubated in IL-2 during that time.  The unwashed cultured cells are then retransfused into the patient intravenously for three successive days.

Of 102 cancer patients receiving IL-2 activated LAK cells who could be evaluated, 8 had complete response, 15 had partial response, and 10 had minor responses.  The median duration of response was ten months among those with partial responses.  One patient was still in remission 22 months after treatment.  Of the eight patients with a complete response, five were suffering from renal cell  cancer with metastases to the lungs following radical nephrectomy.  Two had melanomas with pulmonary metastases and one had a lymphoma. The tumor mases in the lungs shrank dramatically following LAK treatment.

I. R.Tizard.  Immunology an Introduction.  4th edition.  Sanders College Publishing, Harcourt Brace College Publishers, 1995

 

TIL Therapy

Encouraging results with LAK cells led to search for cells that were even more potent against cancer.  Recently such cell has been found, after identifying cells already activated against a patient’s specific cancer. 

Initially it was postulated that if the immune system was aroused against a cancer, the tumor site should have the highest concentration of cancer-sensitive lymphocytes.  Therefore a new technique was developed for isolating lymphocytes from tumors.  In one method a small tumor was surgically removed from the animal, enzymatically digested to separate the cells, and then the cells were cultured with interleukin-2 for several weeks. During that time, what is called tumor-infiltrating lymphocytes (TIL’s) multiplied under the influence of the interleukin-2.   LAK cells generally stop proliferating after about 10 days, but other lymphocytes capable of killing the tumor continued to grow vigorously and eventually replaced the tumor.  These proliferating TIL’s were then studied for their effect in animals. 

The TIL’s that overran the culture turned out to be classic cytotoxic T cells.  Unlike LAK cells, they had the specificity the researchers initially sought.  On exposure to tumor cells in laboratory dishes, such TIL’s often kill only the cells of the tumors from which they are derived and no others.  In fact, they represent the best available evidence that at least some humans with cancer do indeed mount a specific immunologic reaction against their tumor.  When newly isolated cytotoxic TILs were injected into mice, it was found that, on a cell-for-cell basis, they were from 50 to 100 times more effective than LAK cells causing regression of established tumors.  It was also found that the TIL’s were more effective than LAK cells at eliminating cancer in mice with widespread tumors. Human cancer studies showed that 55 percent of the study group responded well to the therapy.  In fact, the response rate was more than twice that seen when LAK cells were used.

S. A Resenberg.  Adoptive Immunotherapy for Cancer. In: Immunology: Recognition and Response.  Readings from Scientific American Magazine. Edited by: W.E. Paul.  W.H. Freeman and Company. New York. 1991

Review Questions

1. Textbook Study Questions

Review questions at the end of the Chapter 24.  The answers with explanations are available at the end of the textbook.

2.  Multiple Choice Questions

1.  One mechanism by which tumors evade immunological destruction is

A) secretion of anticomplementary factors

B)  release of lymphotoxins

C)  production of immunosuppressive molecules

D) reducing their expression of class 1 MHC molecules

E)  alternate pathway cytotoxicity

2.  NK cells develop from which cell lineage?

A) T cell

B)  B cell

C)  myeloid

D) erythroid

E)  none of the above

3.  Macrophage antitumor activity is mainly mediated by

A) interleukin-6 and interleukin-1

B)  tumor necrosis factor and interleukin-1

C)  nitric oxide and interleukin-6

D) nitric oxide and tumor necrosis factor

E)  interleukin-2 and interleukin-1

4.  Immunotoxins are

A) toxic substances released by macrophages

B)  lymphokines

C)  toxins complexed with the corresponding antitoxins

D) toxins coupled to antigens-specific immunoglobulins

5.  The appearance of many primary lymphoreticlar tumors in humans has been correlated with

A) hypergammaglobulinemia

B)  acquired hemolytic anemia

C)  BCG treatment

D) resistance to antibiotics

E)  impairment of cell-mediated immunity

3.  Definitions/short Answer Questions

1.  Tumors and transplants are similar to one another, yet very different. Explain this observation in the context of what the immune system recognizes and the result of this recognition.

2.  The qualities of proliferation and differentiation are essentially all that distinguishes a normal cell from a cancer cell. Explain.

3.  Design an experiment using mice that proves that the immune system provides immunity against tumors.

4.  Distinguish between tumor-specific transplantation antigens (TSTA) and tumor associated transplantation antigens (TATA).

5.  Design an experiment to show Tumor Associated Transplantation Antigens (TATA).

6.  What is the main difference separating cell surface antigens from chemically induced and virally induced cancers? Speculate on why this difference leads to difficulty in designing anticancer vaccines.

7.  What are oncofetal antigens? Are they important in tumor immunity? Why?

8.  What is immune surveillance? All evidence for immune surveillance is indirect. Speculate on how you could get direct evidence.

9.  What immune cells play a role in tumor rejection? Briefly describe how each accomplishes this task. Include such things as cytokines, perforins, ADCC etc.

10. Cancers camouflage themselves to evade antitumor defenses. Pick three possible forms of camouflage that you think are most important, describe them and state why you think they are most important.

11. What are immunotoxins?

12. Surgery, radiation and chemotherapy are the methods most widely used to treat cancer patients. What are the problems with this regimen, and how could immunotherapy overcome these problems? Distinguish between specific and nonspecific immunotherapy.

Where to Go from Here

Congratulations! You have just completed all of the material covered in this course.

As a final review, go back to the objectives in the first 4 lessons and review them. Is the material clear? Do you understand the concepts? If not, go back to the textbook and review the material again. Repeat this process until you have reviewed all of  the objectives in all of the lessons, giving yourself  about a week to complete this process. Once you are confident that you can meet all of the objectives, proceed to the Practice Final Examination.