The immune surveillance theory

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The immune surveillance theory put forward by Thomas in 1959 and redefined by Burnet (1967) states that the immune system is constantly patrolling the body for tumour (abnormal) cells, which are recognized as foreign, and mounts an immune response that results in their elimination before they become clinically detectable (Burnet, 1967). Although this concept remains controversial, a wide range of evidence supports it.

First, cancer patients with tumours infiltrated by many immune cells (e.g. proliferating CD8+ T lymphocytes, macrophages, NK cells)

have better survival than those with few infiltrated immune cells, suggesting that such immune cells are responsible for the improved survival in these patients (Ropponen et al., 1997; Naito et al., 1998; Nakano et al., 2001; Nakayama et al., 2002; Ohno et al., 2002). Second, as described above, the incidence of cancer is higher in older people and in the neonatal period when immune responses are less efficient. Third, the incidence of cancer is much higher in immunodeficient people (e.g. AIDS patients) than in those with a normal immune system. About 40% of HIV-infected individuals develop some form of cancer such as Kaposi's sarcoma (a malignant tumour of the blood vessels in the skin), or lymphoma (a malignant tumour of the lymphatic system) (Scadden, 2003). In addition, the incidence of certain types of cancer (e.g. skin cancers, lymphoma) is increased by four- to 500-fold in patients who have received organ transplants, whose immune systems have been downregulated with immunosuppressive drugs; reversal of the immunosuppression can result in tumour regression (Abgrall et al., 2002; Lutz and Heemann, 2003; Vial and Descotes, 2003). Furthermore, spontaneous regression of malignant tumours occurs in patients with melanoma, renal cell carcinoma, neuroblastoma, lymphoma and hepatocellular carcinoma, in whom the immune system plays an important role (Papac, 1998; Bromberg et al., 2002; Morimoto et al., 2002).

Mechanisms responsible for tumours escaping immune recognition

The proliferation and presence of clinically detectable tumours in cancer patients suggest that such tumours have been able to escape recognition and destruction by the immune system (i.e. the immune surveillance). From examination of sera and biopsies from cancer patients, it has become evident that cancer patients can produce both cell-mediated and antibody-mediated immune responses against tumour cells (Naito et al., 1998; Shimada et al., 2003). However, recent evidence suggests that the immune responses in some patients are either too weak to be effective in eliminating all tumours or, in other cases, too impaired to recognize the original tumours. Indeed, as explained in Chapter 9, the great majority of human tumour antigens are tumour-associated antigens; such antigens are also present in lower amounts on normal cells and are therefore less immunogenic (Kuroki et al., 2002). In addition, several other factors have been identified that can help the tumour cells to escape recognition and destruction by the immune system:

• Loss or downregulation of antigens recognized by tumour cells.

• Downregulation of MHC-I expression from the tumour cell's surface.

• Lack of co-stimulatory molecules (e.g. cytokines and adhesion molecules) which are necessary for T-cell activation.

• Overwhelming mass of tumour antigens and the presence of shed antigens in circulation.

• Increased level of immunosuppressive cytokines (TGFp or IL-10).

• Downregulation of antigen-processing machinery.

In some situations, tumour cells escape immune recognition by losing or downregulating the expression of highly immunogenic antigens (Lollini and Forni, 2003). In other cases, tumour cells have been shown to lose or downregulate the expression of MHC-I molecules, which are essential (see Figure 7.2a) for antigen recognition and cell killing by CD8+ cytotoxic T cells (Natali et al., 1989; Paschin et al., 2003). In addition, antigen presentation by APCs to T cells in the absence of a co-stimulatory signal or mitogenic cytokines (e.g. IL-2) can result in immunological anergy. The release of immunosuppressive cytokines such as TGFp and IL-10 by tumour cells and T cells can suppress the immune response against cancer cells, thus leading to tumour tolerance (Kirkbride and Blobe, 2003).

Immunotherapeutic strategies for human cancer

In recent years, as a result of better understanding of the immune system, including the mechanisms that are used by tumour cells to escape immune recognition and destruction and identification of novel antigens of biological and clinical significance at different stages of the cancer, immunotherapeutic approaches have been initiated in patients with a wide range of cancers (Berd, 1998; Armstrong and Hawkins, 2001; Costello et al., 2003; Waldman, 2003). The overall aim of such strategies is to provide protection against cancer cells, by either amplifying the immune response against cancer cells or correcting and breaking tolerance against tumour antigens via the patient's own immune system.

There are currently two main immunotherapeutic strategies against human cancers, namely the monoclonal antibody-based therapy of human cancer and the development of cancer vaccines. The former strategy has been described in detail in Chapter 9 and is particularly effective in the destruction of extracellular antigens, such as overexpressed HER-2 antigens in patients with metastatic cancer.

In recent years, several types of cancer vaccines have been prepared that are at different stages of clinical development including vaccines containing: (1) intact autologous tumour cells (derived from the patient to be treated) or intact allogeneic tumour cells

(derived from other patients) modified by physical alteration, gene modification (with IL-2, granulocyte-macrophage colony-stimulating factor [GM-CSF]) or mixing with adjuvants (e.g. bacille Calmette-Guerin [BCG] - an attenuated strain of Mycobacterium bovis, or QS-21, a material extracted from tree bark) that boosts the immune response against human tumour cells; (2) crude extracts of tumour cells; (3) purified extracts (e.g. gangliosides in melanoma); (4) peptides (MAGE proteins found in melanoma); (5) heat-shock proteins; (6) dendritic cells pulsed with tumour antigens and co-stimulatory molecules and cytokines; (7) DNA- and RNA-based vaccines; and (8) anti-idiotypic antibodies as surrogate antigens (Pardoll, 1998; Leitner et al., 2000; Berd, 2001; Lundqvist and Pisa, 2002; Davidson et al., 2002: Ehrke, 2003). The major aim of such strategies is to direct tumour killing by inducing cell-mediated (antigen-specific T cell), anti-tumour immune responses in such patients.

The potential of immunotherapeutic strategies for the treatment and prevention of human cancers has generated considerable excitement and interest among tumour immunologists and oncologists worldwide. In particular, the extraordinary capacity of dendritic cells to capture and process tumour antigens, together with their capacity to present the fragments of such antigens in association with MHC-I and MHC-II molecules to CD4+ T cells and CD8+, and therefore their activation, have made them ideal as a source of human cancer vaccines (Figure 7.4). The results of clinical trials with different type of vaccines should clarify the full potential and limitation of each strategy and would ultimately lead to the development of a more effective therapeutic strategy directed against a specific population of cancer patients (Tjoa et al., 1997; Bodey et al., 2000; Bremers et al., 2000; Romero et al., 2002; Sabel and Sondak, 2002; Boon and Van den Enbde, 2003; Ehrke, 2003).

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