Alternative explanations for the phenomena assigned to the immune surveillance theory

Those being skeptical with regard to the immune surveillance theory refer to the alternative explanations for phenomena such as increased tumor incidence in immunodeficiency, spontaneous regression of tumors, and the association of tumor cells with cells from the immune system.

Tumor incidence associated with immunodeficiency

Alternative explanations regarding the increased tumor incidence in immunodeficiency are also entirely plausible. The increased tumor incidence in immunodeficient renal transplant patients is primarily due to an increase in skin cancer (squamous cell carcinoma) and non-Hodgkin lymphoma (the majority being of B cell origin), whereas a substantial increase in the more common cancer types, such as breast cancer, cancer involving the respiratory system, and gastrointestinal cancer, is not observed in these patients. Non-Hodgkin lymphoma and skin cancer in immunodeficiency are associated with a viral etiology (Epstein-Barr virus (EBV) and human papillomavirus (HPV), respectively). It is therefore conceivable either that these viruses are carcinogenic themselves or that the increased frequency of viral infection acts as a cofactor, making the infected cell vulnerable to becoming a tumor cell. With regard to immunosuppression, it should be noted that only parts of the immune system are immunosuppressed (generally the T cell compartment). Similarly, the increased incidence of non-Hodgkin lymphoma in patients with congenital immune deficiencies might be due to an abnormal proliferative response (regulation) of the immune cells, due to genetic aberrations in these patients.

Immune suppressive drugs may also cause the anomalies observed. Patients treated for longer periods with cyclosporine or azathioprine were shown to have chromosomal abnormalities. Immunosuppressive drugs may also have synergistic effects to other carcinogens. Metabolites of azathioprine cause chemical photosensitization. A synergistic effect of azathioprine with ultraviolet light or HPV may explain the high incidence of skin cancer in allograft recipients.

Spontaneous regression of tumors and latency

Because of a lack of knowledge regarding the etiology of spontaneous remissions, such remissions could be associated with a variety of causes (e.g. vascular insufficiency, tumor differentiation or psychosomatic mechanisms) in addition to immunological phenomena. The presence of long latency periods before metastases appear may equally well be due to environmental factors (e.g. lack of adhesion molecules or growth factors), the absence of additional genetic 'hits' required for tumor progression, as to immune mechanisms.

Tumor-infiltrating cells

The observation of an infiltrate of immune cells surrounding tumor cells might be due to a chronic inflammatory response initiated and sustained by cell death. During this process, only occasionally (depending on the proteins expressed by the tumor cells) does an antitumor response occur. This occasional immunogenicity of the tumor cells may also explain the limited successes of immunotherapy of cancer.

In conclusion, inherent with the nature of the theory that neoplasms are eradicated before becoming clinically evident, formal proof either in favor or against the immune surveillance theory is difficult to obtain. It is proven beyond doubt that the immune system is able to mount an immune response against particular tumor cells. However, one can still argue whether all tumor cells which arise are immunogenic, and if an immune response occurs each time tumor cells arise.

See also: Immune surveillance; Immunodeficiency, primary; Immunodeficiency, secondary; Immunosuppression; Immunotherapy of tumors; Tumor antigens; Tumors, immune response to; Tumors, immunological escape of.

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