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Interleukin-10 Gene Polymorphisms and Cancer


Interleukin-10 (IL-10) is a multifunctional cytokine with both immunosuppressive and anti-angiogenic functions. In consequence, IL-10 can have both tumor-promoting and tumor-inhibiting properties. Raised levels of serum and peri-tumoral IL-10 production have been reported in many malignancies, which have been interpreted in support of a role for IL-10 in tumor escape from the immune response. However, gene transfection studies in a number of malignancies argue more convincingly for an anti-tumor function of IL-10, possibly via inhibition of pathways of angiogenesis.

A large number of polymorphisms (primarily single nucleotide polymorphisms (SNPs)) have been identified in the IL-10 gene promoter. Convincing evidence that certain of these polymorphisms are associated with differential expression of IL-10 in vitro and in some cases in vivo have been obtained. While a large number of investigations of possible associations between IL-10 genotypes and immune mediated disease have been performed, the literature with regard to IL-10 polymorphisms and cancer is as yet small, but growing. These published studies include both solid tumors and hematological malignancies and common and less common diseases. In this chapter, the results from 15 studies in 10 different malignancies are reviewed. In 12 of these studies, positive associations between IL-10 genotype or haplotype and disease susceptibility and/or progression were reported. In some of these cancers (for example, cutaneous malignant melanoma, prostate cancer, breast cancer, non cardia gastric cancer and nonHodgkin's lymphoma) genotypes associated with low IL-10 expression were a risk factor for disease or disease progression, while in others (for example, cervical cancer, cardia gastric cancer, post-transplant squamous cell carcinoma of the skin and multiple myeloma), genotypes associated with high IL-10 expression were a risk factor).

All results reviewed should be regarded as preliminary, due to the small sample sizes of almost all of the studies and the limited numbers of IL-10 polymorphisms examined. In addition, few of the studies have examined levels of IL-10 production in vivo in the subjects genotyped. However, the preliminary data obtained thus far indicate that much larger studies are required in a number of cancers, in order to confirm initial results, extend studies to include more detailed genotype/haplotype analysis and to combine genotype and gene expression studies in the same subjects. Such studies will contribute significantly to our understanding of the biological role of IL-10 in tumor development, with implications for cytokine therapy in cancer.


As considered in more detail elsewhere in this volume, Interleukin-10 (IL-10) is a key regulator of immune responses and was originally described as cytokine synthesis inhibitory factor,1 being produced by Th2 cells and inhibiting cytokine production by Th1 cells. Later studies showed that the actions of IL-10 on inhibition of pro-inflammatory cytokine production by both T and NK cells were indirect, acting via inhibition of accessory cell function.2-5 In addition, it was soon shown that IL-10 inhibits a broad range of activated monocyte/macrophage functions, including monokine synthesis, nitric oxide production, major histocompatibility complex (MHC) class II and CD80/CD86 costimulatory molecule expression.6-11 In vitro and in vivo studies revealed pleiotropic activities of IL-10 on B and T cells and, taken together, that a critical function of IL-10 is to suppress multiple immune responses through individual actions on T cells, B cells, antigen presenting cells and other cell types, and to skew the immune response from Th1 to Th2 (reviewed in detail in ref. 12). In malignancy, this might suggest a priori, that IL-10 might promote tumor development, by acting to suppress anti-tumor immune responses, where these occur. However, a number of other findings suggest that the biological properties of IL-10 are more complex than this and IL-10 may have immunostimulatory or immunosuppressive effects, depending upon the assay used, cell types involved and other concomitant immune events,13 therefore the actions of IL-10 on tumor development may be more complex. In particular, animal models suggest that IL-10 can induce NK cell activation and so facilitate anti-tumor responses, leading to tumor cell destruction. 14,15 Evidence for both tumor promoting and anti-tumor functions of IL-10 is briefly reviewed below.

IL-10 and Cancer

There are a number of reports describing elevated levels of IL-10 expression in patients with particular cancers, including malignant melanoma,16-19ovarian cancer20 and other carcinomas, 21-24 lymphoma and myeloma.25,26 These elevated levels have been reported both in the serum and/or tumor lesions. Furthermore, a negative correlation between circulating levels of IL-10 and prognosis has been reported in patients with solid tumors, including lung cancer,22 renal carcinoma24 and gastrointestinal tumors27 and hematological malignancies.28-29 A simplistic interpretation of these data would be that elevated IL-10 levels are associated with suppression of anti-tumor immune responses. However, elevated IL-10 expression can occur for a number of reasons. Production by tumor and other cells may indeed result in suppression of anti-tumor immune responses, but IL-10 may also act as a tumor growth factor, as evidenced by the action of exogenous IL-10 on human melanoma cells lines.30 In addition, IL-10 can also be produced by activated cells involved in anti-tumor immune responses and so may be indicative of a potent anti-tumor immune response. Indeed, it should be noted that elevated IL-10 levels do not correlate with prognosis in all studies31 and in some cases favorable prognosis has been associated with elevated IL-10 expression.32

More convincing data come from studies of IL-10 gene therapy in animal models of tumor growth and establishment, which consistently demonstrate an anti-tumor role for IL-10. In a colon carcinoma mouse model, transfection of tumor cells with IL-10 reduces the malignant potential of the tumor cells and induces a predominant Th2-mediated tumor rejection response. 33 Similarly, IL-10 transfected cell lines derived from mouse mammary adenocarcinoma, 34 ovarian carcinoma,35 malignant melanoma,36 Burkitt's lymphoma,37,38 prostate39 and colon cancers33 show significant inhibition of tumor growth. In support of this, systemic administration of IL-10 has inhibited tumor metastasis in various murine models, including melanomas,14,40 sarcomas and colorectal carcinomas.40

The mechanisms behind these antitumor effects are still incompletely understood. Many researchers attribute the antitumor effects of IL-10 to its effects on NK cell activation,14,15 although actions on T cells,40 macrophages41 and nitric oxide42 have also been implicated. In addition, IL-10 enhances the susceptibility of target cells to NK cell lysis by reducing cell surface MHC expression.43,44 However, an increasing body of evidence suggests that IL-10 exerts an antitumor effect by inhibition of angiogenesis. For example, in vitro studies of prostate tumor cells show that IL-10 stimulates tissue inhibitors of metalloproteinases (TIMPs) and inhibits matrix metalloproteinase (MMP) expression, so affecting induction of angiogenesis.45,46 Similarly, IL-10 gene transfection studies in malignant melanoma have shown that inhibition of tumor growth by inhibition of angiogenesis is accompanied by downregulation of synthesis of vascular endothelial growth factor (VEGF)—one of the most potent angiogenic factors—along with IL-1βtumor necrosis factor-αTNFα IL-6 and MMP-9 (all known to have angiogenic properties) in tumor-associated macrophages.17 In addition, in Burkitt's lymphoma, a lymphoid malignancy, introduction of human or viral IL-10 genes into tumors in SCID mice revealed an inhibition of VEGF-induced neovascularisation of the tumors.37

Accordingly, while the mechanisms remain unclear, there is a considerable and growing body of evidence for the antitumor properties of IL-10 and this may result at least in part from inhibition of angiogenesis, possibly by inhibition of production of angiogenic cytokines, growth factors and MMPs and stimulation of production of inhibitors of angiogenesis. Based on this, several investigators have suggested therapeutic use of IL-10 in cancer patients,14,15,17,40,47 but at present no clinical trials have been performed.

An alternative strategy to determine the role of IL-10 in the development of particular malignancies is via genetic approaches. In recent years a considerable number of genetic polymorphisms have been identified within the IL-10 gene, particularly within the promoter region of the gene. Certain of these polymorphisms have been shown to be associated with differential levels of IL-10 expression. A considerable number of studies have been performed to determine whether IL-10 polymorphisms are associated with susceptibility to a large number of immune-mediated diseases (reviewed in refs. 48 and 49) and a small number of investigations have been performed in solid tumors and hematological malignancies and this literature is briefly reviewed below.

IL-10 Gene Polymorphisms

The IL-10 gene is comprised of 5 exons, spans approximately 5.2 kB and is located on chromosome 1, at 1q31-1q32.50 Due to the critical role of IL-10 in regulating immune responses in health and immune-mediated diseases, a number of groups have pursued intensive studies to identify naturally occurring gene polymorphisms in the IL-10 gene and flanking regions. To date, at least 49 IL-10-associated polymorphisms have been reported in the literature and these are summarised in Table 1. An even larger number of polymorphisms are recorded in single nucleotide polymorphism (SNP) databases (e.g., the Wellcome Trust Sanger Institute/ European Bioinformatics Institute SNP database: Ensembl Genome Browser).

Table 1. IL-10 gene polymorphisims.

Table 1

IL-10 gene polymorphisims.

From Table 1 it can be seen that of the 49 polymorphisms listed, 46 are SNPs, 2 are microsatellite polymorphisms and 1 is a small (3 bp) deletion. Twenty-eight polymorphisms occur in the promoter region of the gene, 20 polymorphisms are noncoding intronic or synonymous substitutions and only 1 polymorphism results in a change in amino acid sequence. The promoter polymorphisms have been subject to the most scrutiny, particularly with regard to possible influences upon gene transcription and expression. For example, the IL-10 -1082 SNP and -1082, -819, -592 haplotype have been reported to be associated with differential IL-10 expression in vitro, with the -1082 A, -819 T, -592 A haplotype associated with decreased IL-10 expression, compared with the - 1082 G, -819 C, -592 C haplotype.55 This is thought to reflect - at least in part - differential transcription factor binding associated with the -1082 SNP.60 In addition, IL-10 R and G microsatellite haplotypes have also been shown to be associated with differential levels of IL-10 expression in vitro.61 Some workers have suggested that as much as 75% of inter-individual variation in IL-10 expression may be due to genetic variation,62 although others believe that the contribution of individual SNPs—such as the best-described -1082 SNP—may be much less than this.60 Accordingly, the role of IL-10 polymorphism in determining susceptibility to and prognostic outcome in nonmalignant immune-mediated diseases has been the subject of intense interest and a plethora of case-control studies have demonstrated a number of positive associations in a diverse range of diseases, including asthma,63,64 systemic lupus erythematosus,52 reactive arthritis65 and outcome of clinical renal,66,67 heart68 and bone marrow transplantation.69 Similarly, other investigations have failed to implicate IL-10 promoter polymorphisms in susceptibility to various diseases including multiple sclerosis,70,71 while in other diseases results are conflicting e.g., rheumatoid arthritis.72,73 Summaries of studies of IL-10 (and other) cytokine polymorphisms and disease have been published by Bidwell et al48 and Haukim et al,49 both of which contain extensive bibliographies.

IL-10 Gene Polymorphisms and Cancer

The literature concerning IL-10 polymorphism in cancer is very recent and is therefore still relatively small, but growing rapidly, with all publications dating from 2001. Results from these studies are summarised in Table 2 and each disease is considered in more detail below. From a casual inspection of Table 2, it will be noted that while all except one study is of case-control design, several studies have also investigated associations between particular IL-10 polymorphisms and markers of disease prognosis. Of the 15 studies listed, 6 have studied the IL-10 -1082 SNP alone and 8 have studied the IL-10 -1082, -819, -592 SNPs and haplotypes in case-control studies (in one study, cases only) of the malignancy in question. The IL-10G and IL-10R microsatellites were examined in the remaining study. Therefore all studies published thus far have focussed upon those polymorphisms for which there is direct evidence for a causal association with differential IL-10 expression (IL-10 -1082), or polymorphisms and haplotypes which act as markers for differential IL-10 expression (IL-10G and IL-10R microsatellites and IL-10 -1082, -819, -592 haplotypes). As yet, no published studies have performed detailed IL-10 SNP analysis or haplotyping across the complete IL-10 promoter and/or gene sequence in any malignancy.

Table 2. IL-10 polymorphisms and cancer.

Table 2

IL-10 polymorphisms and cancer.

In the following consideration of the studies summarised in Table 2, cutaneous malignant melanoma (CMM), prostate (PC) and breast cancer (BC) are considered first, since angiogenesis is crucial for the development of these tumors89 and indeed the extent of angiogenesis correlates with the probability of metastasis and/or prognosis in these malignancies.90-96

Cutaneous Malignant Melanoma

CMM is the most serious cutaneous malignancy and is increasing in frequency among most Caucasian populations, where the most important risk factor is exposure to ultraviolet light.97Relatively little is known of the genetic factors that mediate susceptibility to and prognosis in sporadic CMM, although polymorphisms associated with the melanocortin-1 receptor (MCR1),98,99 CDKN2A,100 XRCC3 DNA repair gene101 and glutathione S-transferase Mu phenotype (GSTM1)102 may be associated with susceptibility to CMM. Polymorphisms associated with the Vitamin D receptor and the cytochrome P450 CYP2D6 genes have been implicated in modulating prognosis in this tumor.103,104 In addition, several lines of evidence suggest that CMM patients develop an immune response to their tumors105 (supported by variable HLA-DQB1 allellic associations with CMM susceptibility and prognosis106,107), although in individuals with CMM, this anti-tumor immune response is insufficient to abrogate tumor development.

Based on the above, and to distinguish whether high constitutive levels of IL-10 have a tumor-promoting or anti-tumor influence in CMM, we have shown that the IL-10 -1082 AA genotype, associated with low IL-10 expression in vitro is associated with both susceptibility to CMM (OR = 1.78) and is a risk factor for more advanced (OR = 2.24) , and poorer prognosis disease, as evidenced by tumor Breslow thickness (OR = 3.67).74 IL-10 -1082, -819, -592 haplotypes associated with low IL-10 expression (ACC/ACC, ACC/ATA and ATA/ATA) were also associated with greater tumor Breslow thickness (OR = 3.63), which is the single most important prognostic indicator in CMM.108 In addition, the IL-10 -1082 GG genotype and IL-10 -1082, -819, -592 GCC/GCC _high expression_ haplotype were associated with noninvasive tumor growth (ORs = 2.42 and 2.31 for noninvasive growth respectively). This study was performed in British Caucasian CMM cases and controls. Some support for these findings is provided by the small, independent study of Martinez-Escribano et al,75 who showed that in Italian CMM patients, the IL-10 -1082, -819, -592 ACC/ATA low expression haplotype was also associated with greater tumor Breslow thickness and was a risk factor for poorer survival. Finally, it should be noted that results from these genetic studies are in accordance with the effects of IL-10 gene transfection in animal models of malignant melanoma, which suggests that intratumor expression of IL-10 abrogates tumor development.36

Although the influence of IL-10 on CMM development is likely to be complex, these results support recent findings that IL-10 has an anti-tumor effect in CMM, possibly via inhibition of VEGF expression and angiogenesis.17 In agreement with this, we have also obtained evidence that gene polymorphisms associated with differential expression of other angiogenic cytokines (in particular, VEGF) may also play a role in predisposition to and tumor growth in CMM.109

Prostate Cancer

In Western Europe and the USA, PC is the most common cancer diagnosed in men and the second most common cause of death with a continuing increase in incidence.110 The evidence that PC has a genetic component is compelling from epidemiological and genetic studies; some high-risk genes have been identified, that when present may predispose a carrier to development of the disease111. Examples of PC susceptibility genes include HPC1 on chromosome 1q24-25,112 HPCX on Xq27-28,113 BRCA1 on 17q21 and BRCA2 on 13q12,114 CAPB at 1p36,115 PCAP on 1q42.2-43116 and most recently ELAC2/HPC2 on chromosome 17p.117 The association between these high penetrance genes and PC susceptibility highlights the complex and multigenic mode of inheritance of PC, yet more common, lower penetrance susceptibility polymorphisms in genes may be implicated in a higher proportion of the sporadic PC disease burden and so have more relevance to public health.

The prostate was originally thought to be an immunologically privileged site. However, there is now good evidence that the prostate has a lymphatic system, can mount inflammatory immune responses and these responses-as evidenced by density of tumor infiltrating lymphocyes-may be associated with prognosis in PC (reviewed in ref. 118). The immune system may therefore play a role in the pathogenesis of PC, via regulation of tumor growth, while evasion of the immune response may play a role in disease progression. In addition, due to the critical role of angiogenesis in PC development93, and based on our findings in CMM, we elected to determine whether polymorphisms in pro- and anti-inflammatory and pro-angiogenic cytokine genes were associated with susceptibility to and/or markers of prognosis in a case-control study of British Caucasian PC patients and population controls. Results indicated that the IL-10 -1082 AA _low expression_ genotype was significantly increased in incidence in the patient group (OR = 1.78), closely paralleling results in CMM.76 This is again suggestive that genetically determined low levels of IL-10 production may be a risk factor in PC, via down-regulation of VEGF synthesis or enhanced lysis of tumor cells by NK cells. Again, results from this genetic study are in accordance with findings from IL-10 gene transfection studies in this malignancy.39

Evidence for a role for polymorphism in pro-angiogenic genes was also provided by this study, which showed significant associations between genotypes associated with low VEGF and low IL-8 expression and protection from PC.

Breast Cancer

BC is by far the most common malignancy affecting Western women. A family history of BC is one of the most important and consistent risk factors, highlighting the role of inherited germline susceptibility genes. In the mid 1990s, two BC susceptibility genes, BRCA 1 (chromosome 17) and BRCA 2 (chromosome 13) were identified.119,120 Mutations that render these genes nonfunctional or absent are inherited in an autosomal dominant manner and confer a high disease risk. However, recent epidemiological studies suggest that BRCA 1 and BRCA 2 mutations only account for a few percent of BC cases.121 It is highly likely that a number of more prevalent, low penetrance genes contribute to BC susceptibility in a larger population of women and are therefore responsible for a greater proportion of the disease burden.121-123

Recent modelling of breast cancer inheritance in a population where BRCA1 and 2 gene carriers had been excluded from the cohort revealed a model of inheritance that is polygenic and provides an estimate that nearly 90% of all breast cancer cases will occur in an identifiable subset of perhaps half the general population.124 As yet, little is known about low penetrance susceptibility genes which contribute to BC susceptibility and only a few have been identified, including genes involved in carcinogen detoxification and oestrogen metabolism.125-127

There is accumulating evidence indicating the presence of peritumoral inflammatory infiltrate in BC, which may reflect-at least in part-an antitumor immune response, while angiogenesis is necessary for the development of BC and the extent of angiogenesis correlates with tumor development and patient survival.94-96 In addition, high levels of IL-10 mRNA are detectable in tumor lesions.128 Accordingly, we have performed a small study of 144 British Caucasian BC patients and 263 controls, for the same panel of SNPs in pro- and anti-inflammatory and pro-angiogenic cytokine genes as studied in PC, but have failed to demonstrate any associations with susceptibility to BC, for any of these SNPs, including IL-10 -1082, save for the TNFα308 GG, which was increased in frequency in the BC group, at a marginal level of significance.77 Conversely, in an independent study of 125 Italian BC patients and 100 controls, Giordani et al78 have reported a significant association between the IL-10 -1082 AA_low expression_ genotype and BC, analogous to our findings in CMM and PC, but have failed to demonstrate any association between the TNFα308 SNP and BC.

Therefore the limited data obtained to date with regard to IL-10 polymorphism and development of BC are equivocal, but suggest that a larger study of IL-10 -1082 and additional polymorphisms is merited in this very common cancer.

Cervical Cancer

Most high-grade cervical neoplasms have been shown to contain oncogenic human papilloma virus (HPV) DNA, although only a small proportion of such cases progress to cervical cancer. Factors-including genetic factors-leading to impaired immune responses to HPV may play a role in determining susceptibility to the development of cervical cancer. In support of this, a number of studies have implicated particular HLA polymorphisms (In particular, HLA-DQB1*03 alleles) in conferring susceptibility to squamous cell cervical carcinoma.129-132 In addition, variation in the secretion of several cytokines, including IL-10, have been reported in the blood and tissues of patients with cervical cancer,133-135 while angiogenesis is also necessary for the development of cervical neoplasia.136

Based on the above, two studies have sought to address whether IL-10 polymorphisms are associated with susceptibility to cervical cancer. In the first published study of 77 Zimbabwean women with histologically proven cancer of the uterine cervix and 69 age- and parity matched controls, the IL-10 -1082 GA genotype was found at a significantly increased frequency of 40.2% in the cases as compared with a frequency of 16% in the controls (P = 0.001). Since only one case and no controls were of IL-10 -1082 GG genotype, and the GA genotype is associated with higher IL-10 expression in vitro than the AA genotype, the authors of this study infer that a genetic predisposition to produce higher levels of IL-10 may play an important role in the pathogenesis of cervical cancer.79 This is consistent with IL-10 contributing to tumor escape from the immune response in the development of this malignancy, but the molecular function of IL-10 in the pathogenesis of HPV infection and cervical cancer may be multifactorial and the authors stress that results should not be interpreted in isolation from studies of other cytokine polymorphisms in this malignancy.79

The second published study examined the frequency of the IL-10 -1082, -819 and -592 polymorphisms in 144 Korean women with invasive cervical cancer and 179 ethnically matched noncancer controls. In this study, all individuals were homozygous for the -1082 AA genotype and only two haplotypes (-1082, -819, -592 ATA and ACC) were observed, neither of which were associated with invasive cervical cancer, nor with serum IL-10 concentration.80 Therefore, in Korean women the IL-10 genotypes studied do not appear to influence susceptibility to invasive cervical carcinoma, but due to the lack of IL-10 -1082 polymorphisms observed in this study group and hence lack of comparability with the Zimbabwean study outlined above, a role for IL-10 polymorphism in the development of cervical cancer cannot be ruled out by this study alone.

Gastric Cancer

Gastric carcinoma remains a common disease worldwide137 and cancers of the upper gastrointestinal tract comprise four distinct entities, namely squamous cell and adenocarcinoma of the esophagus, adenocarcinoma of the gastric cardia and adenocarcinoma of the distal (noncardia) stomach. Environmental and host-related factors interact in disease development, among which Helicobacter pylori infection and cigarette smoking are important environmental risks. Host immunogenetic factors have been shown to be associated with increased risk of gastric cancer and its precursors. In particular, El-Omar and colleagues have shown that functional polymorphisms in the pro-inflammatory IL-1β gene and its receptor antagonist (IL-1RN) are associated with increased risk of noncardia gastric tumors.138,139 These data indicate that genetic control of inflammation and response to Helicobacter pylori infection may be important in the development of upper gastrointestinal cancers in general. Accordingly, in a US-based study group, El-Omar and colleagues have also investigated the role of SNPs in the TNFα IL-1βIL-4, IL-6 and IL-10 genes and risk of development of upper gastrointestinal tract cancers, including esophageal and gastric cancers. Proinflammatory genotypes of TNFα(carriers of -308 A high expression allele) and IL-10 (carriers of the -1082, -819, -592 ATA low expression_ haplotype) were associated with a more than doubling risk of developing noncardia gastric cancers (OR for possession of IL-10 ATA haplotype = 2.5). Carriage of multiple proinflammatory polymorphisms of TNFαIL-1βIL-1RN and IL-10 conferred greater risk, with ORs of 2.8 for one, 5.4 for two and 27.3 for three or four high risk genotypes. In contrast, these polymorphisms were not consistently related to the risk of esophageal or gastric cardia cancers.83 The authors interpret these findings to suggest that a proinflammatory host genotype favors the development of a hypochlorydric, atrophic response to gastric infection with Helicobacter pylori which in turn predisposes to noncardia gastric adenocarcinoma, but not to cardia or esophageal tumors. However, an association of IL-10 _low expression_ genotypes with noncardia gastric adenocarcinoma is also consistent with anti-angiogenic functions of IL-10 and angiogenesis is known to be important in the development of gastric cancer.140

Two similar studies of IL-10 polymorphism in the development of gastric cancer in Taiwanese Chinese have been performed by Wu and colleagues.81,82 In opposition to the study of El-Omar and colleagues,83 the studies of Wu report that the IL-10 -1082, -819, -592 GCC high expression haplotype is associated with the development of gastric cancer taken as a single entity (OR = 2.67), and in particular with cardia cancer (OR = 3.21) and advanced stage of disease (OR = 2.29).82 These results are more consistent with genetically programmed high expression levels of IL-10 contributing to an anti-inflammatory immune response, contributing to tumor escape. However, due to the very different frequencies of IL-10 SNP alleles in the two study groups (US and Chinese), differing environmental factors and associations with different forms of gastric cancer (noncardia v cardia), it is difficult to compare the results from these two principal studies and-as yet-to extract unifying findings with regard to IL-10 polymorphisms and gastric cancer development.

Post-Transplant Squamous Cell Skin Cancer

Malignancies arise in 20 to 40% of transplant recipients within 20 years of receipt of graft.141 Skin carcinomas account for up to 50% of these cancers. Viruses, including HPVs, Epstein Barr virus and human herpes virus-8 are involved in the pathogenesis of post-transplant tumors, especially skin carcinomas, B-cell lymphomas and Kaposi's sarcoma. Impaired host immune defences, resulting from heavy immunosuppression are also associated with an increased risk of malignancy. Genetic risk factors are also suspected. Accordingly, genetic polymorphisms associated with differential levels of cytokine production may have an important effect on tumorigenesis after organ transplantation. In this context, IL-10 plymorphism is of particular interest, since, in addition to the biological functions of IL-10 discussed in some detail above, ultraviolet-induced DNA damage, a risk factor for skin cancer, also increases production of IL-10.142

For the above reasons, Alamartine et al,84 in a French-based study, investigated possible associations between the IL-10 -1082, -819 and -592 SNPs and the occurrence of post-transplant skin cancers in a series of 70 renal transplant recipients who developed post-transplant squamous (SCC) or basal cell carcinoma (BCC), 70 healthy controls and 70 age, sex and immunosuppression-matched renal recipients without cancer. Taken together, IL-10 -1082, -819, -592 haplotypes were differently distributed when comparing cancer patients with unaffected patients and with controls. Results showed that genotypes associated with low production of IL-10 (IL-10 -1082, -819, -592 GCC negative) were less frequent in cancer patients (23% v 47% in unaffected patients), but only in patients with SCC (12%) and not BCC (37%). In addition, genotypes associated with high IL-10 production (GCC homozygous) were more frequent in cancer patients (24% v 11%), but this difference was significant only when comparing all cancer patients, or patients with SCC, with controls. The frequency of GCC homozygosity was not increased when considering patients with BCC with unaffected patients. The predicted correlation between IL-10 genotype and in vitro secretion of IL-10 by mononuclear cells was also confirmed by the same study.

Therefore results from this study suggest that genetically programmed elevated IL-10 production may favor the development of carcinoma-especially SCC-in renal transplant patients, although, as for most of the studies reviewed in this chapter, this result requires independent confirmation or replication.

Hematological Malignancies

Multiple myeloma (MM) is a monoclonal B cell neoplasm, in which immunoglobulin producing malignant plasma cells accumulate in the bone marrow. It is unclear whether genetic factors influence susceptibility to MM or clinical course of the disease. However, IL-10 has been implicated in the growth and differentiation of normal B cells,143 has been shown to be a growth factor for MM cells144 and elevated levels of IL-10 have been reported in patients with MM.26 In addition, IL-10 has been implicated in the pathogenesis of other human B-cell malignancies.25 Accordingly, Zheng et al85 analysed the frequency of IL-10 G and R microsatellite alleles in a series of 73 Swedish Caucasian MM patients and 109 ethnically matched controls. Significantly increased frequencies of the IL-10 G 136/136 and IL-10 R 112/114 genotypes were seen in the MM patients, along with a decreased frequency of the IL-10 R 114/116 genotype. In addition, increased production of IL-10 was detected in the supernatants of lipopolysaccharide-stimulated peripheral blood mononuclear cells from MM patients carrying one or two IL-10 G 136 alleles, compared with other IL-10 genotypes. These results suggest that genetically determined elevated levels of IL-10 production may may a role in the development of MM.

The Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders, with some subtypes rarely transforming to acute leukemia.145 There is increasing evidence for an inflammatory component in the pathogenesis of MDS and an autoimmune mechanism is suggested by response to immunosuppression in some MDS patients.146 Despite this, Gowans et al86 failed to find any association between HLA class I and II, TNFαLTαnd IL-10 polymorphisms with either susceptibility to or disease progression in MDS or secondary acute myeloid leukemia (AML) in a series of 150 UK MDS/AML patients and up to 1000 controls, depending upon polymorphism investigated. Accordingly, this single study provides no evidence for a role for the IL-10 -1082, -819 and -592 SNPs in determining susceptibility to or disease progression in MDS and AML. Conversely, a study by Lauten et al88 showed an association between the IL-10 -1082 GG genotype and a protective effect from poor predisone response in a series of 135 German childhood acute lymphoblastic leukemia (ALL) patients, where prednisone response has high predictive power of survival in childhood ALL.147 These preliminary data suggest that genetically programmed high levels of IL-10 production may be associated with treatment outcome in childhood ALL, although large prospective studies will be needed to confirm this.

Finally, Cunningham et al,87 in an Australian-based study, have reported significant associations between the IL-10 -1082 AA genotype and aggressive nonHodgkin's lymphoma (NHL) (OR = 1.97) and between the -1082, -819, -592 ATA and ACC haplotypes and aggressive lymphoma (OR = 1.65). No association was found between IL-10 genotypes and Hodgkin's disease or less aggressive forms of lymphoma. Results in NHL are in apparent conflict with reports that serum IL-10 level is an important prognostic indicator in this disease, with high levels of viral IL-10 correlating with poor prognosis.28,148 However, the genetic results may be interpreted in several ways. The authors consider that a genetically determined _relative lack_of IL-10 may allow lymphoma to arise or progress under the influence of other pro-lymphoma cytokines, or that in patients with aggressive disease, IL-10 genotypes alone may not be an accurate predictor of of IL-10 production in vivo.


As a multifunctional cytokine with both immunosuppressive and anti-angiogenic functions, IL-10 has both tumor-promoting and tumor-inhibiting properties. In addition, when considering both serum and peritumoral levels of IL-10 production in individual malignancies, interpretation of apparently raised levels of IL-10 requires caution and should not be considered in isolation from source of production and levels of other biologically relevant cytokines. However, gene transfection studies in a number of malignancies argue more convincingly for an anti-tumor function of IL-10, possibly via inhibition of pathways of angiogenesis.

Much endeavor has been directed towards identification of polymorphisms in the IL-10 gene and a large number of polymorphisms-primarily SNPs-have been identified in the IL-10 gene promoter. Convincing evidence that certain of these polymorphisms-in particular the IL-10 -1082 SNP and associated IL-10 -1082, -819 and -592 haplotype-are associated with differential expression of IL-10 in vitro and in some cases in vivo have been obtained. While a large number of investigations of possible associations between IL-10 genotypes and immune mediated disease have been performed, the literature with regard to IL-10 polymorphisms and cancer is as yet small, but growing. These published studies include both solid tumors and hematological malignancies and common and less common diseases. As yet, most of these studies comprise small, single center case-control investigations, which may be prone to sampling bias and type 1 errors. In addition, in most of the 10 malignancies reviewed in this chapter, only from one to a maximum of three studies have been performed in each disease, in a range of human populations and ethnic groups. Despite this, it is perhaps striking that in 12 of the 15 studies reviewed in this chapter, positive associations between IL-10 genotype or haplotype and disease susceptibility and/or progression were detected-albeit with relatively modest Odds Ratios and probabilities. In some of these cancers (for example, cutaneous malignant melanoma, prostate cancer, breast cancer, non cardia gastric cancer and nonHodgkin's lymphoma) genotypes associated with low IL-10 expression were a risk factor for disease or disease progression, while in others (for example, cervical cancer and cardia gastric cancer, post-transplant squamous cell carcinoma of the skin and multiple myeloma), genotypes associated with high IL-10 expression were a risk factor.

At this stage, all of the above findings should be regarded as highly preliminary, due to the small sample sizes of almost all of the studies and the limited numbers of IL-10 polymorphisms examined. In addition, few of the studies have examined levels of IL-10 production in vivo in the subjects genotyped. However, the preliminary data obtained thus far indicate that much larger studies are required in a number of common and relatively common cancers, in order to confirm initial results, extend studies to include more detailed genotype/haplotype analysis and to combine genotype and gene expression studies in the same subjects. In this way, our understanding of the biological role of IL-10 in tumor development will be greatly aided, with implications for cytokine therapy in cancer.


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