Wednesday, February 10, 2016

Foxp3+ Treg-derived IL-35 limits anti-tumor T cell immunity

IL-35 is a cytokine composed of the p35 subunit of IL-12 (encoded by Il12a) and Ebi3 (Ebi3). It was discovered in 2007 at Dario Vignali's lab and since then ~ 200 papers have been published about IL-35, according PubMed database. Most studies indicate that IL-35 has immune inhibitory function.

Now, new study in journal Immunity from the same Dario Vignali's lab provided evidence that Foxp3+ Treg-derived IL-35 inhibits effectiveness of anti-tumor T cell activity, pointing to it as a new immunotherapeutic modality. I am going to highlight the most notable results.

First, the authors showed that tumor (B16 melanoma) growth or its metastasis were inhibited when (a) mice were injected with antibody against IL-35 or when (b) mice lacked IL-35 specifically in Tregs (Foxp3Cre-YFP. Ebi3L/L mouse).

Similar effect of IL-35 blockade on tumor growth was seen in genetically-induced tumor model, in KP mouse, that spontaneously develop lung cancer after adenovirus-Cre delivery (KP mouse contains an activating mutation in K-RAS and a loss of function mutation in p53 controlled by Cre mediated recombination).

Mechanistically, the authors showed that IL-35 blockade improved T cell recruitment into tumor tissue.

Finally, the authors found that presence of Treg-derived IL-35 contributes to T cell exhaustion during tumor growth.

In summary, this study indicate the following scenario: certain tumors recruit Tregs. These Tregs secrete IL-35 and inhibit recruitment of effector T cells and/or contributes to their exhaustion. Blocking of IL-35 could provide immunotherapeutic benefit (interestingly, it appears that IL-35 does not synergize with anti-PD1 treatment in tumor models discussed in this paper).

David Usharauli

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