Immune Surveillance

The hypothesis of immune surveillance was formulated by two prominent immunologists, Lewis Thomas in 1959 (Thomas, 1959) and Mac Farlane Burnet in 1964 (Burnet, 1971). In Burnet's words: "In large long lived animals ... inheritable genetic changes must be common in somatic cells and a proportion of these changes will represent steps toward malignancy. It is an evolutionary necessity that there should be some mechanism for elimination or inactivity of such potentially dangerous mutant cells and it is postulated that this mechanism is of immunological character."

The evolutionary necessity of cancer protection is certainly true, but the unique role attributed to the immune system ignores two salient facts: (1) tumor evolution involves the loss rather than the gain of many functions and (2) the cancer cell phenotype is easily malleable. This does not augur well for the immune recognition of tumors as "nonself" targets. Even if adventitious, immunologically recognizable mutations would occur, they may be readily circumvented by further mutations or phenotypic modulation. There is one important exception, however. Oncogenic proteins of DNA tumor viruses, such as SV40, polyoma, papilloma, and Epstein-Barr virus (EBV), are readily recognized by the immune system as nonself. They are also relatively stable targets since their expression is a prerequisite for the proliferation of the virally transformed cell.

The strongest argument for immune surveillance is provided by the increased incidence of a given tumor in immunodefectives. Three types of human malignancies qualify by this criterion. All of them are virus related: EBV carrying immunoblastoma, papillomavirus-associated cervical, anogenital, and skin cancer, and HHV-8 carrying Kaposi's sarcoma.

The frequency of other tumors does not increase significantly in the immunosuppressed. This is in line with the notion, also supported by research on experimental animals, that spontaneous tumors with no viral involvement are regarded as "self" by the immune system (with skin melanomas as a possible exception). Immunological attempts to influence such tumors are therefore akin to breaking or circumventing tolerance. Current efforts toward that goal include the inhibition of regulatory T cells; the provision of appropriate costimulatory signals; the stimulation of proinflammatory cytokines such as IL-1, IL-6, or IL-12; the activation of dendritic cells, for example, by administering a ligand for a Toll-like receptor; and the attempts to stimulate natural immunity.

If the immune system cannot mount the robust immunity envisaged in the early statements of Ehrlich, Thomas, and Burnet, it is still true that we are strongly protected against cancer development. It is well established that the majority of tumor cells that disseminate during surgery do not give rise to metastasis. This is not necessarily an immune protection, however, as so frequently assumed. The well documented fact that dormant tumor cells can "wake up" years or decades later also speaks against immune killing.

What other mechanisms protect us against cancer? There is evidence for at least four different types of nonimmune surveillance against cancer. Two of them, genetic (DNA repair based and checkpoint control) and intracellular (largely apoptosis related) surveillance, are well established. Evidence for epigenetic surveillance, related to chromatin structure and particularly the stringency of imprinting, has only recently started to emerge. A fourth, already quite strong and rapidly increasing area, intercellular surveillance, points to the importance of the tumor microenvironment.


Tumor risk is highly influenced by mutations in genes that control the fidelity of DNA replication, the efficacy of DNA repair, and the checkpoint controls of chromosome separation. Mutations in these genes, whether identified as point mutations, microsatellite instability (MSI), or loss of heterozygosis, are referred to as mutator mutations.

Xeroderma pigmentosum (XP) is the oldest known case of a specific DNA repair deficiency. It is due to recessive mutation in one of the essential components of the nucleotide excision repair (NER) system, the repairo-some. The latter is composed of 30 different proteins, and its main function is to excise thymidine dimers from UV-exposed DNA in the skin epithelium.

XP patients must protect themselves from light all their lives, but they nevertheless develop multiple skin carcinomas. This points to the paramount importance of DNA repair as a first-line surveillance mechanism.

Hereditary nonpolyposis colon cancer (HNPCC) is due to a defect in one of several DNA mismatch repair (MMR) genes. Some of their products can splice out the mismatched region and insert new bases to fill the gap. MMR defects can be manifested as MSI and are associated with multiple cancers. MLH1 is one of the frequently involved genes. MLH1 mutation in the hereditary cases and epigenetic silencing by dense hypermethylation of the 5' promoter region in sporadic cases can lead to the same MSI phenotype.

These and other examples have identified DNA repair as a robust protection mechanism against cancer.

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