Interleukin10 and Human Cancer

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Expression of IL-10 by Human Cancer

The biological significance of IL-10 production by tumor cells has yet to be fully determined and maybe very much dependent on the type of tissue/organ in which the tumor is developing. A summary of reported observation on IL-10 expression by human cancers is shown in Table 2. IL-10 is often identifiable in freshly excised human tumors including melanoma, ovarian, breast, renal cell, lung, skin, lymphoma, nasopharyngeal and esophageal can-cer.40-52 In the majority of the cases, IL-10 is over expressed preferentially in metastatic lesions (melanoma, ovarian cancer). In addition, several human cancer cell lines constitutively produce IL-10 in vitro suggesting that a large amount of the IL-10 present in vivo in the tumor microenvironment is probably secreted by tumor cells.53 The multitude of autocrine and exocrine effects induced by IL-10 in the tumor and its microenvironment are discussed in the next section and summarized in Figure 1.

Clinical Correlates of IL-10 Activity in Human Cancer

The role of IL-10 in the context of human cancer is complex. A negative correlation between circulating levels of IL-10 and prognosis was observed in patients with solid or hematologic malignancies.10 However, this association may reflect the bulk of IL-10-producing tumor cells in advanced stages. Over-expression of Th2-type cytokines (including IL-10) associated with depressed APC function was observed in tumors unresponsive to immune-chemotherapy.54 In contrast, high IL-10 levels were observed in areas of spontaneous regression of primary melanoma.41 Indirect evidence of the importance of IL-10 as a inhibitor of cancer growth is also suggested by recent work from Howell's group that noticed a higher incidence of melanoma and prostate cancer in individuals bearing a polymorphism in the promoter region of IL-10 associated with enhanced production of this cytokine in response to stimulation of immune cells.55,56 Associations between IL-10 polymorphisms and incidence of other cancers have also recently been described by others in the context of breast57 and gastric cancer58,59 and are discussed more extensively in the corresponding chapter of this book.

The proliferation rate of human melanoma cell lines is enhanced by exogenous IL-10, suggesting that this cytokine might serve as a tumor growth factor.60 In addition, IL-10 immune suppressive effects may allow tumor escape from immune recognition.60-62 The role that IL-10 may play in tumor escape is, however, far from established. In the context of human papilloma virus-related cervical carcinoma, IL-10 enhances synergistically with IL-2 tumor-specific T cell expansion and cytotoxicity by increasing intracellular accumulation of perforin. 3 In a recent

Table 2. Tumor expressing IL-10 in humans

Tumor

Tissue/Cell Type

Location and Biological Significance

Reference

Melanoma

Primary, metastases, cell lines

Selective expression of IL-10 mRNA in tissues of primary melanomas and melanoma metastases. Strong expression of IL-10 mRNA and of biologically active IL-10 was detected in 3 out of 1 3 melanoma cell lines.

Kruger-Krasagakes S et al, 1994

Melanoma

Established melanoma cell lines, freshly cultured primary cell, metastatic melanoma cells

Preferential expression of IL-10 (mRNA and protein) in metastatic lesions and in cultured cells from metastases compared with primary cells indicates an increased spread ing potential of IL-10-secreting melanoma-cell clones

Dummer Wet al, 1996

Melanoma

Small number of melanoma cells segregated by indirect immunomagnetic isolation from regressing and progressing areas of primary tumors.

IL-10 mRNA detected by RTPCR both in progressing and regressing tumor areas. Higher titer of IL-10 in the progression zones.

Conrad CT, 1999*

Melanoma

Pretreatment FNA of responding lesions, metastatic melanoma cell lines

IL-10 mRNA detected by QRTPCR differentially expressed Mocellin S et al, 2001 in pretreatment FNA of responding lesions compared to non responders

Ovarian carcinoma

Tissue biopsy

Selective expression of IL-10mRNA (as detected by PCR assisted mRNA amplification assay) in epithelial ovarian carcinoma tissue compared to normal and ovarian cell lines

Pisa P et al, 1992

Breast carcinoma

Tissue biopsy

IL-10 mRNA expression by RT-PCR

Venetsanakos E et al, 1997

Renal cell carcinoma

Tissue biopsy

Selective expression of IL-10mRNA compared to normal

Nagakomi H, 1995

Table continued on next page

Table continued on next page

Table 2. Continued

Tumor

Tissue/Cell Type

Location and Biological Significance

Reference

Basal cell (BCC), Squamous cell carcinoma (SCC)

Primary tumor tissue biopsy (BCC SCC), tumor cells lines

Detection of IL-10 in tissue and in tumor cell line culture supernatant, neutralization of IL-10 by mAb in tumor / CTL cocultures

Kim J et al, 1995

Squamous cell carcinoma of head and neck

Tissue biopsy

11-10 Protein by IHC

Chandler SWetal,2002

Broncogenic carcinoma

Tissue homogenates, cell lines

Increased levels of antigenic IL-10 in tissue homogenates bronchogenic carcinomas compared with normal lung tissue IHC staining of tumors localized IL-10 to individual tumor cells. IL-10 Supernatants unstimulated human bronchogenic cell lines.

Smith DR et al, 1994

Esophageal cancer

Surgically resected specimens

IL-10 gene expression was significantly correlated with VEGF121 gene expression suggesting that IL-10 stimulates angiogenic factor gene expression.

Nagata J et al, 2002

B,T,NK cell, Hodgkin's lymphoma

Cancer cell, serum

Biologically active protein both viral and human in serum and secreted by cancer cells

Asadullah Ketal, 2003

Primary cutaneous T cell lymphoma

Tissue biopsy

IL-10 protein expression was demonstrated in 73% of HLA-G+ cases, which significantly correlated with HLA-G protein presence HLA-G/IL-10 enhanced coexpression may facilitate the transition from low-to high-grade lymphomas

Urosevic M et al, 2002

Nasopharyngeal

Serum, biopsies

IL-10 protein detected in cancer cells by IHC and in serum by ELISA significantly increased compared to EBV seronegative patients controls

Budiani DR et al, 2002

Non small lung cancer

Surgical specimen

IL-10 mRNA assessed by RT-PCR was significantly correlated with GM-CSF expression

Kamiya T et al, 2003

Non small cell lung cancer (NSCLC)

Tissue biopsy

Normal bronchial epithelial cells constitutively produce IL-10. Lack of IL-10 protein expression by IHC in early stage NSCLC was correlated with worse disease specific and disease free survival than NSCLC expressing IL-10.

SoriaJC et al, 2003

Foreskin Lesions

Figure 1. Immune regulatory role of IL-10 in the tumor microenvironment. An "IL-10-centric" model of tumor immune regulation. Timing of IL-10 appearance from different sources may not be critical for immune balance since IL-10 is constitutively released at least by tumor cells with additional contributions by immune cells. The constitutive concentration of IL-10 and IL-10 R in the tumor microenvironment during tumor progression potentially determines immune activation or immune suppression and the balance between these two immunological vectors ultimately influences the natural history or the response to therapy of individual cancer lesions. Tumor cells could be directly affected by IL-10 naturally released by macrophages, monocytes, NK cells eosinophils or T cells infiltrating the tumor microenvironment. Similarly, autocrine production of IL-10 from tumor cells, IL-10 produced as the result of gene transfer in experimental models or exogenous IL-10 could similarly affect tumor growth. Depending upon the concentration of IL-10 within the tumor microenvironment, the level of IL10R on the tumor and the affinity of IL-10 for the receptor, inhibition or enhancement of tumor growth may occur. The immediate direct effect ofinhibition oftumor growth results from IL-10 up-regulation ofTIMP-2 expression, down-regulation of MMP-2 and MMP-9 with consequent inhibition of micro-vessel formation, and from IL-10 induction of toxic levels of nitric oxide. IL-10 may inhibit cancer growth through down-regulation of MHC/TAP1,2, and increased sensitivity to NK cell killing and tumor elimination through innate immune mechanisms. On the contrary, enhancement of tumor growth may directly occur as the result of IL-10 functioning as growth a factor during autocrine or paracrine secretion. As secondary effect, enhancement of tumor growth may results from immune suppression of mononuclear phagocytes (monocytes, macrophages), T cells and eosinophils. A dramatic effect of IL-10 on tumor growth is the induction ofsuppressor of cytokine synthesis (SOCS)-3 that inhibits macrophage activation resulting in down regulation of innate defense mechanisms. Up regulation of regulatory T cells capable of inhibiting Th1 and Th2 cytokine production, also contributes to tumor escape and progression. It is likely that the presence of IL-10 at concentrations compatible with autocrine or paracrine secretion by tumor or host cells naturally present in the micro-environment of established tumors, may have beneficial or neutral effects on tumor growth. Excessive expression of IL-10 as induced by gene transfer or exogenous administration, may switch the balance toward tumor repression.

study, we linked the treatment-induced behavior of melanoma metastases to their phenotype by serial gene expression analysis of samples obtained by fine needle aspirates (FNA).64 Using this strategy, we measured the mRNA levels of genes with immune regulatory function such as IL-8, IL-10, and transforming growth factor-P1 and -P2 supposed to be constitutively secreted by tumor cells.62 RNA levels were documented before and during therapy with systemic interlukin-2. Surprisingly, we found that IL-10 mRNA was the only cytokine associated with immune responsiveness and was expressed at significantly higher levels in pretreatment FNA samples obtained from immune responsive lesions43 (Table 2). This study, once again suggested that IL-10 may play a role in maintenance of tumor growth in natural conditions but at the same time may precondition the microenvironment to immune responsiveness in the context of systemic immune stimulation.2 A follow-up study on an independent patient population confirmed this finding by identifying a positive correlation between clinical regression and IL-10 protein levels in tumor cells from FNA obtained before therapy.53

The preconditioning effect of IL-10 in humans may be mediated, as animal models suggest, through NK cell activation leading to tumor cell killing, antigen release and APC stimulation by damaged cells.2 At the same time, IL-10 inhibits classical APC maturation which preserves their antigen-uptake function while promoting polarization toward a M2 phenotype that promotes angiogenesis, tissue remodeling and repair65 Finally, IL-10 inhibits recruitment and activation of adaptive immune mediators, which maintain a chronic inflammatory state within the tumor microenvironment. Recently, it has been suggested by animal models that the CXC chemokines inducible protein-10 and monokine induced by IFN-y mediate the local and systemic anti-tumor effects of IL-10 through induction of local inflammation and recruitment of CD4+ cells.66,67 Upon addition of a secondary pro-inflammatory stimulus (i.e., the systemic administration of high-dose IL-2), the balance is shifted toward activation ofAPC with consequent production of chemo attractants, costimulatory molecules and cytokines with prolifera-tive effects on immune cells.68 In this case, APC loaded with antigen act as strong immunogens for the incoming tumor-specific T cells. Obviously, this pro-inflammatory activity is not limited to IL-2 alone as other cytokines may serve as a link between innate and adaptive anti-tumor immunity as recently reviewed.69

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