NK Cells and Macrophages Are Important in Tumor Recognition

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The recognition of tumor cells by NK cells is not MHC restricted. Thus, the activity of these cells is not compromised by the decreased MHC expression exhibited by some tumor cells. In some cases, Fc receptors on NK cells can bind to antibody-coated tumor cells, leading to ADCC. The importance of NK cells in tumor immunity is suggested by the mutant mouse strain called beige and by Chediak-Higashi syndrome in humans, as described in the Clinical Focus in Chapter 14. In each case, a genetic defect causes marked impairment of NK cells and an associated increase in certain types of cancer.

CLINICAL FOCUS

CLINICAL FOCUS

Cancer Vaccines Promise Hope for the Future realization that the vertebrate immune system evolved to distinguish self from non-self led to the notion that our immune system could recognize a tumor as foreign. In fact, a major research effort amongst cancer immu-nologists during the latter half of the 20th century was the identification and characterization of tumor specific molecules, the so-called tumor antigens. This area of research was met with skepticism. First of all, the existence of tumor-specific antigens was questionable; many antigens were identified as tumor specific only to find that other cells also expressed these antigens. Secondly, early investigations in the field of tumor immunology necessarily employed animal models that may or may not be relevant to human cancers. However, with advances in biotechnology, genomics, and proteomics, coupled with our increased understanding of the cellular interactions in the immune system, tumor immunology now offers us the promise of new drugs that will aid in the treatment of cancer. We now understand that tumor-associated antigens do exist and that focusing the cellular arm of the immune system toward the recognition these proteins is a rational approach to the development of a cancer vaccine.

One of the best-studied tumor-immunity models is melanoma. Melanoma has evolved as a model system for several reasons. First of all and paradoxically, most human cancers are difficult to establish in tissue culture, making it difficult to develop in vitro systems for experimental manipulation. Melanoma is relatively easy to adapt to tissue culture, which has led to the identification of several tumor-associated antigens, some of which are unique to melanoma (see Table 22-5). These observations are enhanced by the ability to create cDNA libraries (see Chapter 23) from tumor cells. The cDNAs can be transfected into target cells expressing the appropriate MHC molecules and then used as targets for CTL-mediated killing. Once CTL reactivity is recognized, the transfected cDNA can be isolated and identified as a potential tumor antigen. The ability to isolate genes encoding tumor-associated antigens provides us with the opportunity to use these proteins as immunogens for the induction of tumor-specific responses. Additionally, the identification of tumor-associated proteins allows us to identify peptides that elicit antitumor responses.

Over the past few years, several biotech companies have devised strategies for the development of vaccines against melanoma as well as other cancers. These strategies have one thing in the common; the induction of a cell-mediated response to tumor-associated antigens. Antigens are derived from individual patient tumors or established tumor cell lines. The use of patient-derived tumors is appealing for obvious reasons. The response to that tumor should, in theory, be uniquely directed only at tumor antigens and not other, potentially allotypic, determinants. However, such individualized therapy could be very expensive and time-consuming. In this scenario, the tumor would be biopsied or surgically removed, placed into culture, and then used as an immunogen. Establishing a primary tumor in culture is not easy, even for melanoma, and the procedure can take several weeks. The time factor, coupled with the realization that many tumors are not easy to grow in vitro, places this into the category of "designer therapies" that may or may not be feasible under the reality of managed health care today.

The use of established tumors as the source of the immunogen is much more accessible in cost and practicality. Samples from several tumors can be grown in culture and protein extracts prepared and frozen, providing a source of immunogen for many patients. In addition to reduced costs, this strategy also allows careful assessment of the immunogenic-ity of the tumor antigens found in the cultured cells. It is possible that some tumors may express higher levels of tumor-associated antigens and be more immunogenic than others. Indeed one biotech company in California, CancerVax (www.CancerVax.com), has derived three cell lines that express high levels of over 20 tumor-associated antigens. Additionally, these cells express MHC class I alleles which are represented in the majority of individuals in the population, meaning that intracellular antigens will be presented properly. Cells are irradiated to render them incapable of cell division and used as irradiated whole cells for immunization. The advantages of this approach lies in the ability to standardize the immunogen as well as reducing the cost.

Antigen presentation is a critical feature of any immunization strategy and one way to enhance to immunization against tumor antigens is to manipulate the fashion in which the antigen is presented. Professional antigen-presenting cells such as dendritic cells are excellent candidates to employ in vaccination protocols. Several companies have developed novel uses for dendritic cells in cancer therapy. Den-dreon (www.Dendreon.com), a Seattle-based company, first isolates dendritic-cell precursors from patient blood, then introduces the immunogen into the dendritic cells and returns the antigen-pulsed dendritic cells to the bloodstream of the cancer patient. This company, through genomics-based drug discovery, has identified tumor-associated antigens prevalent on a wide variety of cancers. Thus the

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CLINICAL FOCUS

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dendritic-cell therapy can be tailored to a variety of different tumors. A variation on this theme currently is being tested by Genzyme Molecular Oncology (www. genzymemolecularoncology.com). Their approach also uses dendritic cells, but rather than employing already-defined antigens, clinical trials are underway where dendritic cells from the patient are fused, using polyethylene glycol, with inactivated tumor cells taken from the same patient. The advantage of this technique is that the hybrid cell has the antigen-presenting capability of a dendritic cell but also contains the antigens from the patient's tumor cells. The dendritic cell processes these tumor antigens and efficiently presents the processed antigen to the immune system of the patient.

A different but equally promising approach to the design of cancer vaccines comes from observations made many years ago that tumor cells are immunogenic—animals injected with killed tumor cells do not grow tumors when challenged with live tissue. When the basis of this protective immuno-genicity was explored, it was found that heat-shock proteins (HSPs) are critical in providing protection. Furthermore HSPs were found to carry immunogenic peptides, thus acting as molecular chap-erones. But how do HSP/peptide complexes in tumor tissue prime the host immune system? Recent data demonstrate that HSPs bind CD91, a receptor found primarily on APCs such as dendritic cells as well as on macrophages. In this scenario, HSP/peptide complexes from tumor cells bind the CD91 on

APCs, are internalized, and unexpectedly, the antigen is processed and is thought to re-emerge as peptide/MHC class I complexes on the APC, resulting in the priming of a CD8+ T-cell response. This would not be the predicted response, since the exogenous antigens are almost uniformly presented by class II MHC molecules. However, an impressive amount of experimental data demonstrates that HSPs isolated and purified from tumor tissue are a potent inducer of tumor-specific CTLs. These observations have led to phase III clinical trials conducted by Antigenics (www. antigenics.com) of HSP/antigen com plexes as immunogens for kidney cancer as well as melanoma. The mechanism by which HSP/antigen complexes bound to CD91 are delivered to the class I presentation machinery is not well understood, but it is clear that HSP/antigen complexes, when presented to APCs, result in the vigorous activation of CD8+ T cells.

The promise for cancer vaccines appears very bright. Genomics and pro-teomic methodologies provide novel tools for identifying tumor antigens. Additionally, there is a variety of approaches available to engage the immune system to respond to tumor antigens. The past decade has seen a rapid increase in the number of biotech companies directed at identifying cancer vaccines, and the number of companies in phase II or phase III clinical trials invites an air of optimism about this area of clinical research.

Excise tumor

Excise tumor

Excise Tumor Dendritic Cells

Use tumor cell line

Mix killed tumor cells or proteins extracted from tumor cells with dendritic cells from patient

Return dendritic cells and tumor antigens to patient

Use tumor cell line

Mix killed tumor cells or proteins extracted from tumor cells with dendritic cells from patient

Return dendritic cells and tumor antigens to patient

Cancer vaccine design. Tumor cells are removed from the patient and placed in culture. Alternatively, established tumor-cell lines are chosen and placed into culture. Tumor cells are inactivated and mixed with dendritic cells from the patient and injected back into the patient as immunogens. An alternate approach is to prepare extracts or antigens from the tumor cells and inject these, in addition to dendritic cells, into the patient.

Numerous observations indicate that activated macrophages also play a significant role in the immune response to tumors. For example, macrophages are often observed to cluster around tumors, and their presence is often correlated with tumor regression. Like NK cells, macrophages are not

MHC restricted and express Fc receptors, enabling them to bind to antibody on tumor cells and mediate ADCC. The antitumor activity of activated macrophages is probably mediated by lytic enzymes and reactive oxygen and nitrogen intermediates. In addition, activated macrophages secrete a cytokine called tumor necrosis factor (TNF-a) that has potent antitumor activity. When TNF-a is injected into tumor-bearing animals, it has been found to induce hemorrhage and necrosis of the tumor.

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