Interleukin-35 Restrains Lymphocytic Infiltration and T Cell-Dependent Anti-Tumor Immunity

Interleukin-35 Restrains Lymphocytic Infiltration and T Cell-Dependent Anti-Tumor Immunity

A new study published in the journal Immunity indicates that interleukin (IL)-35 inhibits the recruitment of effector anti-tumor T cells and suppresses their function in the tumor microenvironment.

IL-35 belongs to the IL-12 family of cytokines. It is a dimeric protein composed of two subunits – p35 and EBI3, which are shared with other IL-12 family members, specifically IL-12 and IL-27.

IL-35 is secreted by regulatory T-cells (Tregs) and exerts immunosuppressive effects mostly through an inhibition of T cell proliferation and function.

Over-expression of IL-35 has been found in a variety of malignancies and recent research suggests that IL-35 promotes cancer growth by enhancing angiogenesis and inhibiting CD8+ T cells via TGF-β production.

In the Immunity study Meghan Turnis and colleagues from the Departments of Immunology at the University of Pittsburgh and the St. Jude Children’s Research Hospital, Memphis, TN demonstrate that the tumor microenvironment is characterized by a substantial enrichment of IL-35+ Treg cells.

According to the authors their results suggest that Treg cells are the major, and perhaps, the only source of IL-35 in the tumor microenvironment.

Importantly, the study indicates that the tumor-associated IL-35 contributes to reduced antigen-specific T cell infiltration, decreased effector immune function and memory, and increased tumor burden.

This is achieved mostly by the T-cell exhaustion in tumors, driven by IL-35, as the result of the increased expression of several inhibitory receptors such as PD1, TIM3 and LAG3.

The authors argue that their results may reveal an important and previously unrecognized mechanism for immune evasion – namely, the inflammatory milieu-mediated enrichment of IL-35+ Treg population within the tumor microenvironment.

According to the authors, it is highly likely that IL-35 is more prominently utilized as suppressive mechanism in cancer than in any other inflammatory or autoimmune disease or condition.

Source: Immunity. 2016, 44:316. doi: 10.1016/j.immuni.2016.01.013. Epub 2016 Feb 9.
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