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

Abstract

Summary 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‐β (TGF‐β) 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‐β, 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.

A tritherapy combination of a fusion protein vaccine with immune‐modulating doses of sequential chemotherapies in an optimized regimen completely eradicates large tumors in mice

“…[9][10][11] Another most successful strategy of tumor-induced immune evasion is the recruitment, expansion and activation of CD4þCD25þ FoxP3þregulatory T cells (Tregs). They exist naturally at low numbers but have been documented to increase in patients or animals with malignancies and are capable of suppressing both the innate and the adaptive immune responses in the microenvironment through contact-dependent mechanisms or IL-10 and TGF-b secretion.…”

Mechanisms of tumour escape from immune surveillance

“…The interaction of soluble phosphatidylserine with PSR receptors on the surface of macrophages causes the release of antiinflammatory mediators, such as IL-10, TGF-β, or prostaglandin E2 (PGE2) (26). Some cytokines which have an antiproliferative and pro-apoptotic effect on normal cells remain inactive against tumour cells.…”

“…Moreover, it is hypothesised that tumour cells exhibiting high MHC I antigen expression may evade apoptosis by a mechanism associated with an increased level of heat shock protein HSP90 in the cell nucleus (15). Disturbances in the elimination of apoptotic cells lead to the formation of autoantibodies, resulting in a pseudo-autoimmune status, which in turn can initiate the generation of regulatory Treg lymphocytes inhibiting the antitumour response of T lymphocytes (26).…”

“…An increased number of immature MDSCs have been observed in the peripheral blood and lymph nodes of human patients with breast, head, neck, and lung cancers. Immature TiDC not only do not initiate an antitumour response involving T lymphocytes, but are actually inhibitors of such a response, causing a state of peripheral tolerance for tumour cells (26).…”

“…This is mainly because cancer cells have a variety of strategies to escape from immune surveillance (53). Escape mechanisms of tumour cells include avoidance of recognition and modulation of the immune functions of effector cells, usually leading to immunosuppression, which facilitates tumour progression and metastasis (15,26).…”