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Evidence that the immune system perceives self-derived tumour antigens as “s e lf’

comes from experimental animal models. For example, in animal models where mice

melanocyte antigens induced vitiligo (Bowne et a l, 1999; Colella et al., 2000; Kara et

a l, 1995; Naftzger et al., 1996; Overwijk et al., 1999). In addition, clinical

observations have suggested that the appearance o f vitiligo during melanoma

progression or after therapy is correlated with an improved prognosis (Houghton et

al., 2001), Thus, antitumour immune responses and autoimmune responses could be

viewed as opposite faces o f the same coin (Nanda and Sercarz, 1995). If this is

indeed the case, understanding the mechanism o f how self tolerance is broken to

cause autoimmune disease may be the clue for designing an effective anti-tumour

vaccine.

From the model proposed above (section 1.5.10) describing the response threshold for

signal 1 and signal 2 to trigger peripheral T cell activation, it is likely that a high

signal 2 would be required in order to elicit a response to an antigen providing a low

signal 1. Indeed, means o f enhancing anti-tumour responses through the use o f

adjuvants have been investigated for more than a century.

The role o f adjuvant: introducing signal 2

By definition, an adjuvant is a substance that non-specifically enhances the immune

response to an antigen. Adjuvants are believed to work by providing an artificial

‘danger’ signal which drives APC activation, so that captured tumour antigen can be

presented in an ‘immunogenic’ form, i.e., providing signal 2 to the T cell (Fuchs and

Matzinger, 1996).

The first example o f the use o f adjuvants in tumour immunotherapy was Coley’s

sporadic anti-tumour regression [reviewed in (Starnes, 1992)]. Sixty years later,

Lindenmann and Klein showed that vaccination w ith influenza virus infected tumour

cell lysates generated enhanced systemic immune responses against a challenge with

the original tumour cells (Lindenmann and Klein, 1967). They termed this approach

“xenogenisation”. It was thought that a burst lymphokine production in response to

influenza antigens resulted in amplification o f normally weak responses to the poorly

immunogenic endogenous tumour antigens. The response generated was shown to be

critically CD4^ T cell dependent. More recently, the concept o f presenting

“adjuvants” at the same site as tumour antigens has been tested with some success

(Chiodoni et al., 1999; Davis, 2000; Melcher et al., 1998; Tamura et al., 1997). For

example, BCG immunisation enhanced rejection o f some tumours, particularly

bladder carcinoma [reviewd in (Davis, 2000)]. Other approaches include

immunisation with tumours transduced with various cytokines, o f which GM-CSF has

produced the greatest degree o f T cell immunity relative to irradiated nontransduced

tumour cells [reviewed in (Greten and Jaffee, 1999)]. Other cytokines that stimulate

innate immunity, such as IL-15 and type I IFNs, m ust also be more thoroughly

evaluated in this context. Other strategies include the genetic engineering o f tumour

cells to express MHC and costimulatory molecules that are critical for T or N K cell

activation (Cayeux et al., 1995; Townsend and Allison, 1993). In animal studies it

has already been shown that transfection o f tumours w ith B7-1 and MHC class II or

cytokines, or blockade o f CTLA-4 results in immunity against wildtype tumour

Removing the safeguards: suppressing the suppressing mechanisms

The immune system has many safety mechanisms for preventing self-tissue

destruction in order to avoid autoimmune disease. A number o f regulatory or

suppressor T cell subsets maintain self-tolerance and represent potentially formidable

barriers to successful anti-tumour immune responses. These include NKT cells

(Godfrey et al., 2000), CD25^CD4^ T cells (Sakaguchi, 2000a; Sakaguchi, 2000b)

and C D Saa^ yô T cells (Hanninen and Harrison, 2000). NKT cells can prevent

autoimmune diabetes in NOD mice (Hammond et al., 1998) and CD25^CD4^ T cells

mediate protection against autoimmune gastritis (Sakaguchi, 2000a; Sakaguchi,

2000b).

Accumulating evidence suggests that these safe-guarding regulatory cells have a role

in inhibiting tumour immunity, and that depletion o f these cells results in improved

cancer diagnosis. For example, NKT cells were shown to prevent complete tumour

regression in a mouse model by inhibiting CTL-mediated anti-tumour immunity in an

IL-13 dependent manner (Terabe et al., 2000). Depletion o f CD25^CD4^ T cells can

abrogate immunological unresponsiveness to syngeneic tumours in vivo, resulting in

spontaneous tumour-specific CTL and NK cell cytotoxicity (Onizuka et al., 1999;

Shimizu et al., 1999). This CD25^CD4^ subset appears to suppress the activation and

proliferation o f other CD4^ and CDS^ T cells in an antigenic nonspecific manner

through direct contact with APCs (Sakaguchi, 2000a; Sakaguchi, 2000b). In addition,

depletion o f yô T cells has also been shown to facilitate CTL- and N K cell-mediated

tumour rejection (Seo et al., 1999), although it is not clear whether these are the same

as the CDSaa"^ yô T cells that prevent autoimmune diabetes (Hanninen and Harrison,

suppressor or regulatory cells may be beneficial for treatment o f cancer. This may

involve a simple approach such as transiently depleting these cells or inhibiting their

effector molecules (e.g., IL-13 for NKT cells). Thus, a strategy that incorporates both

the enhancement o f tumour antigen-targeted responses, and the suppression o f

regulatory functions o f the immune system m ay result in promoting tumour rejection