Interleukin10 in Cancer Models

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Experimental cancer models are of particular interest because in most circumstances they seem to support a role for IL-10 as a powerful anti-cancer agent. Theoretically, this surprising anti-cancer activity could be rationalized in two ways. First it could be accepted that IL-10 is an immune suppressive anti-inflammatory agent and, this could slow cancer progression by antagonizing inflammatory processes within the tumor microenvironment that could be beneficial for cancer growth. It has been suggested by animal models that inflammation may be beneficial to tumor growth;20 the presence of inflammatory bioproducts in the tumor microenvironment such as metalloproteinase-9 or CD4+ cells may promote a vasculogenic switch or induce other critical events favorable for tumor progression21,22 An opposite view may propose a pro-inflammatory role for IL-10 that could lead to cancer rejection. While the answer to this opposite interpretation of experimental models is not available, it may be of interest to carefully review reported observations. Experimentally, IL-10 consistently demonstrates anti-tumor properties in vivo7,8,23-29 (Table 1). Most researchers attribute its anti-tumor activity to NK cell activation8,23 although cytotoxic T lymphocytes may be synergistically involved through maintenance of a CD8+ anti-tumor response.30,31 Finally, tumor rejection could also be observed in the context of systemic Th-2 responses.29,30 Yet, a direct stimulatory activity of

Table 1. IL-10 in animal models

Tumor Type Used in Experimental Model

IL-10 Delivery Method

Immune andTumor Effect/ Mechanism of Action

Finding

Reference

Hamster ovarian tumor

Transtection local implant

Local anti-tumor effect

Inhibition of tumor growth

Richte G et al, 1993

Spontaneous mammary carcinoma

Transtection local

Induction of anti-tumor immune response

Protection

Giovarelli M etal, 1995

Tumor

Transtection local implants

Induction of anti-tumor immune response

Protection

Barth RJ etal, 1996

Various types of established (7 day) murine tumors

Systemic

Induction of anti-tumor immune response

Treatment

Berman RM etal, 1996

B1 6 melanoma

Transduction subcutaneous local implants

Local anti-tumor effect, NK cell inhibition of tumors

Protection

Gerard CM et al, 1996

Murine mammary cancer

Transtection local subcutaneous implants

NK-dependent inhibition of tumor

Inhibition of tumor growth

Kundu N et al, 1996

B1 6 and spontaneous melanoma lung metastases

Systemic (I.P.)

NK-dependent inhibition of tumor

Inhibition of tumor growth

Zheng LM etal, 1998

NK-dependent inhibition of tumor MHC I down regulation

Inhibition of tumor metastasis Kundu N and

Fulton AM, 1997

Breast cancer cells

Transduced local

Recruitment of leukocytes

Inhibition of tumor growth

Di Carlo E etal, 1998

Murine mammary tumors

Transtection* local

Elevated levels of nitric oxide

Inhibition of tumor growth

Thomas E and Fulton AM, 1998

CT26 colon carcinoma cell

Transduction local implants T cell-dependent inhibition ot tumor

Inhibition of tumor growth

Adris S et al, 1999

A375 human melanoma subcutaneous and pulmonary metastases

Transtection local xenografts

Local anti-tumor effect, inhibition of TIM, VEGF, IL-1 b, IL-6

Inhibition of tumor growth

Huang S etal, 1999

ß-galactosidase systemic express- Systemic (I.P.) ing 3-day pulmonary metastases

Adjuvant to poxvirus-based vaccine

Treatment

Kautam HL etal, 1999

Human prostate cancer vertebral metastases

Systemic d.M.) xenografts

Inhibition of vasculogenesis, enhancement TIMP2, inhibition of MMP2,9

Inhibition of tumor growth

Stearns ME et al, 1999

Ovalbumin expressing subcutaneous implants

Systemic (I.P.)

Adjuvant to peptide-pulsed APC vaccine

Protection and treatment

Fujii et al, 2001

I.M.: intra-muscular injection; I.P.: intra-peritoneal injection.

IL-10 on adaptive immune effector cells remains to be convincingly demonstrated. It has been suggested that IL-10 may enhance susceptibility of target cells to NK cell lysis by reducing the surface expression of major histocompatibility antigens.32,33 IL-10 also increases the recruitment of macrophages and neutrophils34 and inhibits cancer growth by hampering tumor an-giogenesis and invasiveness through induction of metalloproteinase inhibitors.23,24,34,35 In a colon carcinoma mouse model, the transfection of tumor cells with IL-10 reduces the malignant potential in the context of a predominant Th2-type immune response.29 Transfection of mouse mammary adenocarcinoma34,36 ovarian carcinoma37 and melanoma38 cell lines with IL-10 elicits loss of tumorigenicity and increases immunogenicity accompanied by the induction of a strong lymphocyte and antibody-dependent immune memory.

In summary, experimental models strongly support a role for IL-10 as a mediator of tumor regression. While local administration (tumor transfectant models) predominantly inhibits tumor growth, systemic IL-10 administration has protective and/or curative effects. Although the mechanism(s) responsible for anti-tumor properties remains unclear, it seems that IL-10 stimulates effector functions by enhancing tumor cell killing by NK and, perhaps, CD8+ T cells. This is in line with the hypothesis that the primary role of IL-10 is to induce destruction of abnormal cells with secondary beneficial effects on antigen presentation.39

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