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Anti-cancer versus cancer-promoting effects of the interleukin-17-producing T helper cells.

Hemdan NY.

Immunol Lett. 2013 Jan;149(1-2):123-33. 

Department of Zoology, Faculty of Science, University of Alexandria, 21511 Moharram Bey, Alexandria, Egypt. [email protected].

 

Abstract

Research on T helper 17 (Th17) cells with regard to immunoediting has revealed elusive results. Whereas enhanced Th17 response and related molecules such as interleukin (IL)-17, IL-21, IL-22, IL-23 and STAT3 accompanied tumor induction and progression, finding that tumor growth/stage was negatively correlated with increased infiltration of Th17 cells in the tumor mass has prompted elucidation of various antitumor mechanisms elicited by Th17 and their related molecules. The pro-tumor efficacy of Th17 response included promotion of neutrophilia and induction of angiogenic (e.g. VEGF, MMP2 and MMP9) and anti-apoptotic factors (e.g. Bcl-XL), as well as expansion and activation of myeloid-derived suppressor cells, which facilitate generation of tumor-specific regulatory T cells. Other tumor immunogenic settings revealed anti-tumor pathways including induction of cytotoxic activity, expression of MHC antigens, the ability Th17 cells to reside within the tumor, and to convert into IFN-{Gamma} producers. Notably, Th17 cell related molecules exert indirect pro- or anti-tumor effects via inducing viral persistence or mediating protective mechanisms against bacterial and viral infection. Herein, the recent literature revealing such immunoediting events mediated by Th17 cells and their associated molecules as delivered by various experimental regimens and observed in cancer patient are revised, with a focus on some proposed anti-cancer therapies.

Copyright © 2012 Elsevier B.V. All rights reserved.

 

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Additional information 

In a response to the exciting developments in the arena of tumor immunology witnessed in the last decade, the paper briefly described commitment and plasticity of Th17 cells and focused on their contributions in the context of mediating pro- and anti-tumor mechanisms. As potent inflammatory cells, characterized by their signature cytokine IL-17 and master transcription factor RORgt, Th17 are implicated in mediating various inflammatory and autoimmune diseases and participate in building the link between infection and cancer. The discrepancy of the Th17 cells’ efficacy has been attributed to tumor micro-environmental changes along the course of tumorigenesis, various tumor immunogenicity as well as heterogeneity and plasticity of Th17 cells. Quite anticipated, however, is the residence of Th17 cells within the tumor and their conversion into Th1-like cells.

The data presented are expected to open new horizons when combined to the extensive knowledge of chemotherapeutic perspectives and recent breakthroughs in tumor immunology. Most intriguingly may be targeting TGF-b, IL-17 and IL-22 signaling via autologous cancer vaccines. As a key decision maker in the commitment program and reciprocal regulation of Th17/Treg cells, it is a striking task of TGF-b to favor induction of Th17 or, in different contexts, Treg cells and thereby pro- or anti-inflammatory responses. While it is known that TGF-b exerts multiple crucial functions in the body, emphasized by the fact that its receptor is ubiquity expressed also on tumor cells, similar to other Th17 cells-related molecules including IL-22R, it has so far been possible to pinpoint its specific role as a target of anti-cancer therapy, though its use connected with great complications due to its pleiotropic trait. Notably, elucidating the contributions of TGF-b and other Th17-related molecules to immunoediting should consider the phenotypic changes of Th17 cells accompanying tumor progression as well as in various contexts including tumor immunogenicity, tumor types, location and positivity of infection. Specifying such individual TGF-b-responsiveness at various settings and their effects on various cancer-related processes at Treg and Th17 cells’ polarizing conditions may help attain promising potentials.

Ongoing studies aiming at delineating the effect of autologous ex vivo primed Th17/Treg cells on growth of cancer cells may yield exciting new information. However, the so far inability to attain optimal culturing conditions that mimic the natural niche together with the consequent alteration of the native anti-microbial responses and self tolerance likely limits the clinical use of such cell-based therapies; accompanying prophylactic measures may extend such boundaries.