Interleukin-35 Restrains Anti-Tumor Immunity

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

Interleukin-35 – 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.

Regulatory T (Treg) cells specialize in the maintenance of self-tolerance and prevention of autoimmunity, however, they also restrain critical tumor-specific T cell responses.

The ultimate goal of cancer immunotherapy is to tip the balance away from Tregs and toward tumor-specific T cell activity without causing significant adverse events, such as inflammation and autoimmune complications. To enhance cancer immunotherapy, we require a better understanding of the dominant suppressive mechanisms used by Tregs, especially those that might be selectively utilized only within the tumor microenvironment.

A role for Tregs and their secreted cytokines, interleukin-10 (IL-10), and transforming growth factor beta (TGF-β), in T cell exhaustion in tumors and viral infections has been suggested. However, it remains unclear whether Tregs can directly promote exhaustion of antigen-specific T cells. Reversal of CD8+ T cell exhaustion and efficient control of viral load was noted following dual blockade of Tregs and PDL1 or IL-10 and PDL1.

Elucidation of inhibitory molecules that contribute to the suppressive tumor microenvironment, and yet exhibit a limited role in peripheral immune homeostasis, is highly desirable as it might lead to the development of effective, targeted immunotherapies with reduced adverse events.

Tregs suppress effector cells by numerous mechanisms, one of which is secretion of inhibitory cytokines. One such inhibitory cytokine is IL-35.

Interleukin-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.

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

IL-35 also induces the conversion of conventional T cells into a suppressive, IL-35-producing CD4+Foxp3 induced regulatory T cell population (iTr35 cells). Multiple IL-35+ cell types have been described in tumor-bearing mice and patient samples, and forced expression of IL-35 in the tumor microenvironment can drive enhanced tumor growth. However, the physiological impact of IL-35 on the unmanipulated tumor microenvironment has not been examined and the mechanism by which IL-35 functions in tumors remains obscure.

Over-expression of interleukin-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 tested the hypothesis that interleukin-35 produced by Tregs contributes substantially to the suppressive tumor milieu and that depletion will enhance tumor-specific immunity.

The authors 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 interleukin-35 in the tumor microenvironment.

Importantly, the study indicates that the tumor-associated interleukin-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 interleukin-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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