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Review
. 2006 Oct;119(2):254-64.
doi: 10.1111/j.1365-2567.2006.02430.x.

Cancer immunosuppression and autoimmune disease: beyond immunosuppressive networks for tumour immunity

Ryungsa Kim  1 , Manabu Emi, Kazuaki Tanabe
Affiliations
Review

Cancer immunosuppression and autoimmune disease: beyond immunosuppressive networks for tumour immunity

Ryungsa Kim et al. Immunology. 2006 Oct.

Abstract

Cancer immunosuppression evolves by constitution of an immunosuppressive network extending from a primary tumour site to secondary lymphoid organs and peripheral vessels and is mediated by several tumour-derived soluble factors (TDSFs) such as interleukin-10 (IL-10), transforming growth factor-beta (TGF-beta) and vascular endothelial growth factor (VEGF). TDSFs induce immature myeloid cells and regulatory T cells in accordance with tumour progression, resulting in the inhibition of dendritic cell maturation and T-cell activation in a tumour-specific immune response. Tumour cells grow by exploiting a pro-inflammatory situation in the tumour microenvironment, whereas immune cells are regulated by TDSFs during anti-inflammatory situations--mediated by impaired clearance of apoptotic cells--that cause the release of IL-10, TGF-beta, and prostaglandin E2 (PGE2) by macrophages. Accumulation of impaired apoptotic cells induces anti-DNA antibodies directed against self antigens, which resembles a pseudo-autoimmune status. Systemic lupus erythematosus is a prototype of autoimmune disease that is characterized by defective tolerance of self antigens, the presence of anti-DNA antibodies and a pro-inflammatory response. The anti-DNA antibodies can be produced by impaired clearance of apoptotic cells, which is the result of a hereditary deficiency of complements C1q, C3 and C4, which are involved in the recognition of phagocytosis by macrophages. Thus, it is likely that impaired clearance of apoptotic cells is able to provoke different types of immune dysfunction in cancer and autoimmune disease in which some are similar and others are critically different. This review discusses a comparison of immunological dysfunctions in cancer and autoimmune disease with the aim of exploring new insights beyond cancer immunosuppression in tumour immunity.

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Figures

Figure 1
Figure 1
Cancer immunosuppressive network initiated from primary tumour site and extending to secondary lymphoid organs and peripheral vessels. Tumour-derived soluble factors (TDSFs), such as vascular endothelial growth factor (VEGF), act as strong chemoattractants that induce immature myeloid cells (iMCs), including immature DCs (iDCs) and macrophages, from bone marrow. The iMCs are recruited to a tumour site in which they are biochemically and functionally modulated, whereby they gain immunosuppressive activity and resistance to apoptosis in the tumour microenvironment. Tumour-associated immature DCs (TiDCs) and macrophages (TAMs) can be re-circulated to secondary lymphoid organs and peripheral vessels in the immunosuppressive network, whereas some of the tumour-associated DCs (TADCs) are committed to apoptosis. VEGF inhibits differentiation of thymic precursors, which leads to thymic atrophy.
Figure 2
Figure 2
Different pathways for dysregulated immune responses in cancer and autoimmune disease initiated by impaired clearance of apoptotic cells by macrophages. In autoimmune disease, defective apoptotic cell clearance causes accumulation of DNA–IgG immune complexes, which provoke an immune response through Toll-like receptor 9 (TLR9), leading to tissue injury. Unfortunately, the Treg cells are decreased and dysregulated. In contrast, an impaired clearance of apoptotic cells in cancer produces autoantibodies, which increase the regulatory T (Treg) cells and inhibit T-cell activation, causing immunological tolerance. The immunological tolerance is produced by tumour-derived soluble factors (TDSFs) and immature dendritic cells (iDCs), which inhibit DC and T-cell activation, and exclusively inhibit the DNA–IgG immune complex-induced pro-inflammatory responses needed for an immune response. Immunological ignorance is produced by reduced levels of tumour antigens.
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