Abstract
Multiple innate and adaptive immune effector cells and molecules partake in the recognition and destruction of cancer cells to protect against growing tumors, a concept that is known as cancer immunosurveillance. Unfortunately, cancer cells are capable of avoiding this process by immunoselection of poorly immunogenic tumor cells variants along with subversion of the immune system and thus shaping both the tumor and its microenvironment. Cytokines represent part of the complex pattern of the immune response which can assist the development of cancer as well as to eliminate it. Simultaneously, a large number of cytokines may be involved in the complex interactions between host and tumor cells where this dynamic cross-talk, between tumors and the immune system, can either regulate tumor growth or tumor growth, invasion and metastasis take place. In this review, we are stressing on the interface between infiltrated immune cells and tumor cells with the emphasis on the bidirectional activities of specific cytokines: IFN-γ, TGF-β and IL-17 within the tumor microenvironment and their role in shaping it. In addition, the significance of modulating such cytokines in favor of anti-tumor response is discussed and merits the use of mixture of targeted modulators to overcome the network complexity of cytokines in the tumor microenvironment.
Highlights
The failure of the immune system to recognize and eradicate cancer cells may partly be a result of insufficient immunological activation
Contrariwise, as tissue becomes cancerous pathological interactions between cancer cells and host immune cells in the tumor microenvironment and lymphoid organs create an immunosuppressive network that protects the tumor from immune attack leading to tumor growth, progression as well as invasion and metastasis which is basically due to a deranged relationship between tumor and stromal cells [3,4,5]
Conclusions and future directions It is clear that IFN-g, IL-17 and TGF-b are capable of exerting multiple effects within tumor microenvironment site, many of the exerted effects are contextual compelling further investigations in that regard along with any attempt of their modulation that should be approached with a definite knowledge of the initial level of cytokines and their complex interaction with particular type of tumors and the immune cells
Summary
The failure of the immune system to recognize and eradicate cancer cells may partly be a result of insufficient immunological activation. IL-17 promoted the growth rate and tumorigenicity of human cervical tumors transplanted into athymic nude mice [85]; knockdown of the IL-17 receptor in 4T1 mouse mammary cancer cells decreased tumor growth in vivo [86]; and IL-17 depletion delays development of chemically induced papillomas [55] These effects seem to be driven by a pathway of IL-17 inducing IL-6 production by both neoplastic and stromal cells, which successively leads to activation of STAT3 [83]. The latter observations were correlated with IFNg R deficiency or neutralization of IFN-g and IFN-g response to induce the expression of TNF-a, IL-6, TGF-b during the papilloma promoting stage This stresses that the differential behavior of IL-17 within inflammatory versus non-inflammatory solid tumors and opens a new strategy for suppressing these cells in inflammation-induced solid tumors via down regulating SMAD3/4 and STAT3 signaling pathways. IFN-g is correlated with several direct and indirect antitumor properties and tumor responsiveness to IFN-g is necessary for IFN-g-dependent inhibition of tumor angiogenesis by CD4+ T cells
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