The transformation of a normal cell to a neoplastic cell is a complex process that can involve chromosomal alterations, genetic mutations, and failure of growth control mechanisms. A cell that is transformed to a neoplastic cell may have an altered antigenic makeup. Such a cell may not resemble a normal cell to the immune system. T cells may not recognize the neoplastic cell as "self". Tumor antigens may appear as foreign antigens and elicit an immune response. Sometimes, neoplasia results in overexpression of a normal gene product, and the antigen elicits an immune response when presented in this abnormal fashion.

Immune surveillance may play a role in protection against neoplasia. The recognition of neoplastic cells by the immune system may lead to elimination of those cells before they have had a chance to grow and establish themselves and become clinically apparent. The evidence for this mechanism comes from the observation that persons with immunodeficiency conditions are more likely to develop neoplasms.

The major immune response to tumors comes from cytotoxic CD8 cells. Since tumor cells often do not express costimulators or do not express class II MHC molecules that would aid in activation of CD4 helper cells, a tumor immune response is dependent upon tumor cell processing by APCs such as macrophages which present class I MHC molecules to the CD8 cells along with costimulators. This process is called "cross presentation" since the APC processes the tumor cell and presents antigens to the CD8 cell which induce an immune response back to the tumor cell. Vaccines that present tumor antigens in this way can induce an immune response.

In contrast, NK cells and macrophages do not have a major effect upon tumor cells. CD4 cells play an insignificant role in tumor immune responses. Antibody production by B cells can be demonstrated in many tumors, but it often has minimal effectiveness against the tumor, particularly if the response is polyclonal, with lower titers of weak antibodies. Even the cytotoxic effect of CD8 cells may be minimal because tumor antigens can be weakly immunogenic.

Like micro-organisms, tumor cells are proliferating out of control of the host. Like micro-organisms, this proliferation rate brings with it the potential for new mutations to develop. Like antibiotics applied to infectious agents, the use of chemotherapy drugs and immune responses can kill many cells, but can select out those which are resistant, and the resistant cells will continue to proliferate. Resistant cells may not express the original tumor antigen, or they may not express class I MHC molecules. Tumor cells may produce cytokines that suppress immune responses.

The goal of immunotherapy is to target the abnormal cells specifically with a highly directed imune response, which would not damage normal cells. This would avoid the problems with chemotherapy and radiation therapy, both of which are directed at tumor cells, but also damage normal cells to some extent. The immune response would also seek out the tumor cells, regardless of location. The would avoid the problem with surgery, where success is measured by the ability to dissect around the tumor and remove it all, which is dependent upon tumor size, borders, and location.

Case Presentation:

History: A 50 year old woman has a routine checkup at which time her physician palpates a right breast lump. This lump is about 2 cm in size and is quite firm but non-tender. There is no palpable axillary lymphadenopathy. She has no other physical examination findings of note. She remembers that a paternal aunt had a breast cancer diagnosed at about her age, and she is quite concerned about the lump.

What can you do next?

A fine needle aspirate of the lump can be performed, or an excisional biopsy. A fine needle aspirate can be performed quickly and safely to obtain a working diagnosis. The FNA yields cells consistent with carcinoma. This is followed by lumpectomy with axillary node sampling. The tissue diagnosis is infiltrating ductal carcinoma, and none of the three nodes obtained shows evidence for carcinoma.

What else can be done with the tissue?

One can determine hormone receptor status and HER2 status that will give an indication of potential useful therapies. One can do flow cytometry to give an indication of the biologic behavior of the tumor. Immunohistochemical staining of the tumor shows that the cells are negative for estrogen and progesterone receptor but positive for HER2. By flow cytometry, the cells show a high S-phase with a moderate degree of aneuploidy.

What is the significance of these findings?

The lack of ER and PR receptors suggests that hormonal treatment with a drug such as tamoxifen will not have significant benefit. However, the positive HER2 status suggests that use of the monoclonal antibody trastuzumab will be of benefit. The moderate aneuploidy and high S-phase suggest that the tumor will have some aggressiveness.

Explain the biology of these findings.

About a third of breast cancers have a mutation in the oncogene known as HER2/neu (c-erb B2). The HER2 gene encodes for an epithelial growth factor receptor on the cell membrane that stimulates cellular proliferation. Normal cells do not express this gene product. There is a correlation between HER-2 positivity and high nuclear grade and aneuploidy in the carcinoma cells. The drug trastuzumab is a monoclonal antibody directed against HER-2 positive breast cancer cells. This same form of therapy has also been applied to viral infections.

Staining for HER2-neu (C-erb B2), with a Score of 3