The Immune System And Cancer

THE INTERRELATIONSHIP OF IMMUNE RESPONSE, OLD AGE AND HIGH INCIDENCE OF CANCER

In recent years, several factors have been associated with the development of human cancers including smoking, alcohol, diet, air pollution, infectious agents (viruses and bacteria), chemicals, radiation and hereditary factors (see Chapter 2). The treatment of normal cells with these factors results in the mutation of a wide range of genes, such as tumour suppressor genes or genes coding for growth factor, growth factor receptors, motility and invasion factors. Such mutation can result in turn in malignant transformation of normal cells via the expression or release of either abnormal products or a high level of normal products (Hanahan and Weinberg, 2000).

Since the incidence of cancer increases rapidly in old age, ageing is another important factor associated with human cancers. Around 65% of all cancers are diagnosed in people over the age of 65 (see Chapter 2). While the increasing accumulation of mutations in genes over time is one factor contributing to the high incidence of cancers in old age, recent evidence suggests that malfunction of the immune system may also contribute (Ginaldi et al., 2001; Burns and Leventhal, 2000; Effros, 2003). It is well established that with increasing age there is deterioration of the immune response (i.e. immunosenescence), which results in increased susceptibility to infection, insufficient responses to vaccines and a high level of autoimmune disorders (Lords et al., 2001; Stacy et al., 2002; Burns, 2004). In particular, one of the common alterations in old age is a decline in T-cell mediated immune responses. The decline in CMI with age is a multifactorial phenomenon and could be due to: (i) a decrease in the population of naive (resting) T-lymphocytes, with a concomitant increase in the population of antigen-specific memory T-cells (i.e. exhaustion of immune resources); (ii) the poor proliferative response of T-cells to mitogens; and (iii) a decrease in the expression of the co-stimulatory molecule (e.g. CD28) on T-cells, together with an increase in the expression of inhibitory molecule on CD4+ helper T-cells (Franceschi, Bonafe and Valensin, 2000; Appay and Rowland-Jones, 2002; Effros, 2003). While there is no significant change in the antibody-mediated immune responses and the innate immune response is largely unchanged or even up-regulated in old age, a decline in the T-cell-mediated immune responses, such as those mediated by CD4+ helper T-cells (Figure 8.2), can reduce the overall immune response against cancer cells (Miller, 1996; Lords et al., 2001; Chen, Flurkey and Harrison, 2002; Kovaiou and Grubeck-Loebenstein, 2006).

THE IMMUNE SURVEILLANCE THEORY

The immune surveillance theory put forward by Thomas in 1959 and redefined by Burnett states that the immune system is constantly patrolling the body for tumour (abnormal) cells, which are recognized as foreign, and that when they are found it 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 the idea.

First, cancer patients with tumours infiltrated by many immune cells (e.g. proliferating CD8+ T-lymphocytes, macrophages, NK cells) have a better survival rate 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 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 400-500-fold in patients with organ transplants, whose immune systems have been down-regulated with immunosuppressive drugs, and reversing 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 which the immune system plays an important role (Papac, 1998; Bromberg, Siemers and Taphoorn, 2002; Morimoto et al., 2002).

MECHANISMS RESPONSIBLE FOR TUMOURS ESCAPING IMMUNE RECOGNITION

The proliferation and presence of clinically detectable tumours in cancer patients suggests 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, Ochiai and Nomura, 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, only able to recognize the original tumours. Indeed, as explained in Chapter 10, the great majority of human tumour antigens are tumour-associated antigens, and such antigens are also present in lower amounts on normal cells and are therefore less immunogenic (Kuroki et al., 2002). Several other factors have been identified that can help the tumour cells to escape recognition and destruction by the immune system (Table 8.4). In some situations, tumour cells escape immune recognition by losing or down-regulating the expression of highly immunogenic antigens (Lollini and Forni, 2003). In other cases, tumour cells have been shown to lose or down-regulate the expression of class-I MHC molecules, which are essential (Figure 8.2) for antigen recognition and cell killing by CD8+ cytotoxic T-cells (Natali et al., 1989; Paschen et al., 2003). Antigen presentation by antigen-presenting cells 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 TGF^ and IL-10 by tumour cells and T-cells can suppress the immune response against cancer cells, leading to tumour tolerance (Kirkbride and Blobe, 2003; Rabson, Roitt and Delves, 2005).

IMMUNOTHERAPEUTIC STRATEGIES FOR HUMAN CANCER

In recent years, due to 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 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, either by amplifying the immune response against cancer cells or by correcting and breaking tolerance against tumour antigens using 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

Table 8.4 Factors which may help tumour cells to escape immune recognition

• Loss or down-regulation of antigens recognized by tumour cells.

• Down-regulation of class-I MHC 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 (TGFB or IL-10).

• Down-regulation of antigen processing machinery.

the development of cancer vaccines. The former strategy is described in detail in Chapter 10, and is particularly effective in the destruction of extracellular antigens, such as overexpressed HER-2 antigens, in patients with breast cancer.

In recent years, several types of cancer vaccine have been prepared, including vaccines containing: (i) 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, GM-CSF) or mixing with adjuvants (e.g. BCG, an attenuated strain of Mycobacterium bovis, or QS-21, a material extracted from tree bark) which boost the immune response against human tumour cells; (ii) crude extracts of tumour cells; (iii) purified extracts (e.g. gangliosides in melanoma); (iv) peptides (MAGE proteins found in melanoma); (v) heat-shock proteins; (vi) dendritic cells pulsed with tumour antigens and co-stimulatory molecules and cytokines; (vii) DNA and RNA-based vaccines; and (viii) anti-idiotypic antibodies as surrogate antigens (Pardoll, 1998; Leitner, Ying and Restifo, 2000; Berd, 2001; Lundqvist and Pisa, 2002; Davidson, Kitchener and Stern, 2002; Ehrke, 2003). The major aim of such vaccines is to direct tumour killing by inducing cell mediated (antigen-specific T-cell) anti-tumour immune responses in patients. The extraordinary capacity of dendritic cells for capturing and processing tumour antigens, together with their capacity to present the fragments of such antigens, in association with MHC class I and MHC class II molecules, to CD4+ T-cells and CD8+ T-cells, leading to their activation, have made them ideal as sources of human cancer vaccines (Figure 8.4; Buchsel and DeMeyer, 2006).

In June 2006, the Food and Drug Administration (United States) approved the use of a vaccine called Gardasil against human papillomavirus (HPV), to protect women against cervical cancer, precancerous lesions and genital warts. Cervical cancer is the second most common cancer in women and kills more than 288 000 worldwide each year. More than 95% of invasive cervical cancer is caused by human HPVs (McLemore, 2006). Gardasil is developed by Merck & amp; Co. and is effective against HPV types 16 and 18, which cause more than two-thirds of cervical cancer, and HPV types 6 and 11, which are responsible for 90% of genital warts. Gardasil is a recombinant quadrivalent vaccine containing a mixture of the viral-like particles derived from the L1 capsid proteins of HPV-6, HPV-11, HPV-16 and HPV-18, and an aluminium-containing adjuvant. The results of four clinical trials conducted in 21 000 women and teenage girls have shown that Gardasil is nearly 100% effective in preventing precancerous cervical, vaginal, vulvar and genital lesions caused by HPV-16 and HPV-18, and 99% effective in preventing genital warts caused by HPV-6 and HPV-11. Gardasil was approved by the FDA for girls or women aged 9 to 26, and is given as three injections over a six-month period (Widdice and Kahn, 2006). A second HPV vaccine called Cervarix is in the final stages of development by GlaxoSmithKline and encouraging results have been reported with this bivalent (HPV-16 and HPV-18) vaccine (Speck and Tyring, 2006). GlaxoSmithKline filed Cervarix for approval with the European Union regulators in September 2006. It is expected to be approved in the United States and other countries in early 2007.

Dendritic cell

Antigen fragments

Activated CD8+ cytotoxic T-cell (Tc) induce cell killing

(2) Co-stimulatory signal

(2) Co-stimulatory signal

Antigen fragments

Activated CD8+ cytotoxic T-cell (Tc) induce cell killing

Activated CD4+ T-cells secrete a wide range of cytokines (e.g. IL-2, IL-4 and IL-5) that amplify both CMI and AMI

molecules

Activated CD4+ T-cells secrete a wide range of cytokines (e.g. IL-2, IL-4 and IL-5) that amplify both CMI and AMI

Processed antigens I > Q Self MHC Class-I [ Self MHC Class-II \

molecules

CD4+ T-cell receptor

CD8+ T-cell receptor

Figure 8.4 Therapeutic strategy using dendritic cells as a source of cancer vaccine. Dendritic cells express high levels of both class I MHC and class II MHC molecules on their cell surface. They can be harvested from cancer patients, loaded with human tumour antigens, pulsed with co-stimulatory molecules and returned to patients. Such cells can then present the tumour antigen fragments, in association with class I MHC, to cytotoxic CD8+ T-cells and therefore mediate tumour cell killing by CMI. In addition, some of the antigen processed by dendritic cells can be presented in association with class II MHC molecules to CD4+ helper T-cells, which secrete a wide range of cytokines that help cell killing via CMI and AMI and activate macrophage cell killing (see Figure 8.2).

Unlike Gardasil, Cervarix does not protect against HPV-6 and HPV-11 and therefore will not prevent genital warts. The HPV vaccines are highly immunogenic, provide protection by generating anti-HPV antibodies and have the potential for reducing the incidence of cervical cancer by 70% (Widdice and Kahn, 2006). The results of ongoing clinical trials with different types of vaccine should clarify the full potential and limitation of each strategy and could ultimately lead to the development of an effective therapeutic strategy directed against a specific population of cancer patients (Tjoa et al., 1997; Bremers et al., 2000; Bodey et al., 2000; Romero et al., 2002; Sabel and Sondak, 2002; Boon and Van den Enbde, 2003; Ehrke, 2003; Girard, Osmoanove and Kieny, 2006; Widdice and Kahn, 2006).

IMMUNE SYSTEM IN PATIENTS UNDERGOING CHEMOTHERAPY AND RADIOTHERAPY

All the immune cells of our body (e.g. neutrophils, lymphocytes, monocytes, NK cells) are developed from stem cells in the bone marrow. In the bone marrow, there is approximately 1 stem cell for every 100 000 blood cells. Neutrophils account for about 54-63% of all white blood cells and are the first immune cells to arrive at the site of infection and the first line of defence against invading pathogens. Their numbers in circulation do not change with age in normal individuals (see above). Since they have a short half-life in the blood, the bone marrow produces about 1011 neutrophils a day. Lymphocytes are also very important in mediating adaptive immune responses against both intracellular and extracellular antigens and cancer cells. About one thousand million lymphocytes die and are replaced by the stem cells in the bone marrow every day.

One of the common and most dangerous side effects associated with an intensive course of chemotherapy and radiotherapy is bone marrow suppression and a consequent reduction in the number of white blood cells (leucocytes) in the blood, a condition called leucopenia (Kubota et al., 2001; Hood, 2003). In particular, febrile neutropenia is a common complication of cancer chemotherapy which can cause death in 4-21% of cancer patients (Young and Feld, 2000; Ray-Coquard et al., 2003). With advances in genetic engineering, recombinant forms of haematopoietic cytokines, also called colony stimulating factor (CSF), have been generated which stimulate the proliferation and differentiation of different populations of white blood cells. For example, the human granulocyte colony stimulating factor filgrastim has been shown to be effective in reducing neutropenia, decreasing its severity and duration, reducing hospitalizations and the incidence of infection, and improving quality of life in patients undergoing chemotherapy (Valley, 2002). A modified version of filgrastim, called pegfilgrastim, has been developed which has a much longer serum half-life and therefore requires less frequent administration (Crawford, 2002; Hood, 2003; Rader, 2006).

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