IMMUNOLOGY - Roitt I. - Mir 2000

Chapter 20. Tumor Immunology

IMMUNOLOGICAL SURVEILLANCE

Immunological surveillance is most effective against Viruses rather than tumor Cells

The hypothesis put forward by Burnet and Thomas states that The Immune System constantly monitors the body for the appearance of altered cells and destroys them upon recognition. Thus, according to this concept, an antitumor Immune Response is triggered at an early stage of tumor development and ensures its eradication in most cases before clinical manifestations occur. These scientists also suggested that the immune system plays a crucial role in arresting tumor growth and promoting the regression of already established tumors. Various types of data have been cited in support of these views.

✵ Autopsy findings may reveal a higher incidence of tumors than clinical manifestations indicate.

✵ In many cases, tumors are infiltrated by lymphocytes, and sometimes this can be a favorable prognostic sign.

✵ Spontaneous tumor regression can occur.

✵ Tumors most frequently arise in newborns and elderly individuals, i.e., when the immune system Functions less effectively.

✵ Tumors frequently develop in immunosuppressed individuals.

At first glance, such evidence seems compelling; however, upon closer analysis, the core premise of the theory—the association between immunosuppression and an increased incidence of neoplastic disease—becomes questionable. Much of the available data comes from observations of Kidney transplant recipients, with follow-up periods extending up to 20 years in many cases. These immunosuppressed patients exhibit an increased incidence of various tumor types, some of which appear to be of viral origin (Fig. 20.1). The risk of developing many other non-viral tumors is also elevated, though only slightly. This implies that the immune response primarily prevents the spread of potentially Oncogenic Viruses, whereas immunological surveillance is relatively ineffective against non-viral tumors. In healthy individuals infected with the Epstein-Barr virus, the virus persists in the body throughout life alongside a strong cytotoxic T-Cell response against it. In immunosuppressed individuals, enhanced viral Replication and the shedding of Viral Particles into secreted fluids occur. Consequently, a normal immune response restricts viral propagation (Fig. 20.2).

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Fig. 20.1. Across all types of immunodeficiency, the probability of developing tumors of the lymphoid system increases the most. The Epstein-Barr virus (EBV) plays a role in The Development of many of these tumors. In most adults, EBV persists throughout life without any clinical manifestations. The incidence of most non-virus-associated epithelial malignancies does not increase in immunosuppressed or immunodeficient patients.

Fig. 20.2. In healthy individuals, EBV infects B lymphocytes, but the spread of infection is prevented by Tc cells and Antibodies that destroy infected cells and free virus. In immunosuppressed patients and certain patients receiving the immunosuppressive drug cyclosporine, the virus replicates and infects an increasing number of B cells. It also acts as a B-cell mitogen; therefore, under immunosuppression, infected B cells tend to proliferate more rapidly. Chromosomal translocation in infected B cells can lead to malignant transformation.

The assumption that immunological surveillance is directed predominantly against viruses rather than tumors is also supported by data from animal experiments. For instance, athymic (nude) mice, as well as mice with immunosuppression induced by antilymphocyte serum administration, show no overall increase in tumor incidence; however, the majority of these animals develop tumors caused by the small DNA polyoma virus, which rarely induces tumors in normal animals. This does not imply that an immune response fails to develop against most tumors altogether, but rather that it is apparently relatively late and ineffective.

Tumor Antigens can be recognized by Cells of the immune system or by antibodies

In humans, a viral link has been established for only a few types of malignancies (Fig. 20.3), yet among them, Liver and cervical cancers are widespread causes of mortality worldwide. Targets for recognition during an antitumor immune response can include not only viral antigens but also so-called tumor-associated antigens—components of tumor cells that are altered (in Structure or expression) relative to normal cells of the body. Extensive evidence points to genetic alterations—Mutations, Gene Amplification, chromosomal deletions, and translocations—occurring in the cells of most, if not all, tumors. Some of these genetic aberrations lead to the expression of altered molecules on tumor cells, while others result in the overexpression of normal molecules. Such changes can be detected either by identifying the host immune response or experimentally by immunizing animals of other species with tumor material.

Fig. 20.3. The Epstein-Barr virus is associated with Burkitt's lymphoma, a disease endemic to equatorial Africa, and with nasopharyngeal carcinoma, endemic to southern China. This endemic distribution points to The Role of additional factors, such as genetic or environmental influences, in tumorigenesis. Adult T-cell leukemia is prevalent mainly in Japan and the Caribbean basin.