Immune Surveillance

Immune surveillance is a theory that the immune system patrols the body not only to recognize and destroy invading pathogens but also host cells that become cancerous. Perhaps potential cancer cells arise frequently throughout life, but the immune system usually destroys them as fast as they appear. There is some evidence for this attractive notion. There is also evidence that the immune system mounts an attack against established cancers although it often fails.

• antigens expressed by cells infected with oncogenic viruses, such as
  • human papilloma viruses (HPV — a risk factor for cervical cancer
  • KSHV, the virus that can cause Kaposi's sarcoma
  • Epstein-Barr virus (EBV) — predisposes to Burkitt's lymphoma
  • hepatitis B — predisposes to liver cancer
• Host gene products that are overexpressed or expressed in inappropriate cells.
  • MAGE-A3
  • NY-ESO1 a protein that is produced by several types of tumors (e.g., melanoma, lung and breast cancers) but is not expressed by normal cells (except those in the testis, which is an immunologically privileged site).
  • HER2 ("Human Epidermal growth factor Receptor 2") a growth factor receptor found on some tumor cells (some breast cancers, lymphomas).
• Host gene products that are structurally altered by somatic mutation.
  • All B-cell receptors for antigen (BCRs) qualify as potential neoantigens ("new" antigens). Each developing B cell becomes coated with identical antigen receptors that have been synthesized by a number of processes that are described at this LINK. The result of this programed somatic mutation is a BCR with an amino acid sequence that is probably unique and has never been "seen" by the immune system as "self".

    Most lymphomas are malignant clones of a B cell. In principal, their BCR could serve as a target for destruction by T cells if fragments of the receptor, nestled in an MHC molecule, are "presented" to a T cell. Link to Antigen Presentation. In some lymphomas studied, the patient's T cells did respond and were able to kill the malignant cells (in vitro).

  • A mutated version of the gene (IDH1) encoding the protein isocitrate dehydrogenase type 1 is frequently found in several types of cancer. In mice, a vaccine presenting a peptide including the mutant sequence elicits a Th1-cell response that slows tumor growth.
  • A mutated version of a protein that binds with ERBB2 expressed in a carcinoma is recognized by the patient's tumor-infiltrating lymphocytes (TILs), and these Th1 cells can destroy the tumor cells. Let us examine some of the other evidence for immune surveillance.

Immunodeficient Mice

• have an increased incidence of spontaneous tumors;
• are more susceptible to the induction of tumors by chemical carcinogens.

Normal Mice

When mice with a normal immune system are given very low doses of a chemical carcinogen, a few develop rapidly-growing tumors but many do not. However, it turns out that malignant cells are present in the healthy animals as well, but something is holding them in check. That appears to be the adaptive immune system because, treating them with

• monoclonal antibodies targeting
  • CD4⁺ T cells (Th1) and
  • CD8⁺ T cells (CTL)
  or
• monoclonal antibodies against interferon-gamma (IFN-γ) or interleukin 12 (IL-12)

Control animals treated with antibodies that did not target T-cells or their functions remained healthy.

Immunodeficient Humans

• AIDS patients
• transplant recipients.

A revealing example: Both recipients of a cadaver kidney from a woman, who had been seemingly cured of her melanoma 16 years before, developed melanomas that were genetically the woman's. The recipient's failure to reject those cells was because of the immunosuppressive measures they were receiving so as not to reject her kidney. She must have harbored melanoma cells all those years with her immune system keeping them in check.

Immunocompetent Humans

Cancer patients whose tumors contain large numbers of tumor-infiltrating lymphocytes (TILs), e.g., Th1 cells and/or cytotoxic T lymphocytes (CTLs) and/or NK cells cope with their disease better than patients with only small numbers of these cells.

Why Does Immune Surveillance Fail?

Perhaps most of the time it doesn't. Perhaps visible cancers represent a rare failure of a system that has been eliminating transformed cells throughout life.

But if that is true, what led to the rare failures?

• reduced expression of tumor antigens
• reduced expression of
  • class II MHC molecules needed to display tumor antigens to CD4⁺ Th1 cells [Link]
  • class I MHC molecules needed to display tumor antigens to CD8⁺ cytotoxic T lymphocytes (CTLs) [Link]
• reduced efficiency of loading antigenic peptides into MHC molecules [Link]
• secretion of immunosuppressive cytokines (e.g., Transforming Growth Factor-beta — TGF-β)
• recruitment of immunosuppressive Treg cells.

Whatever the importance of the body's innate response to cancer cells, there is no longer any question that the immune system can be manipulated to help against tumors. Some of the methods employed are described on a separate page: Cancer Immunotherapy.