Interleukin-35 as an Emerging Player in Tumor Microenvironment

Xue, Wenhua; Yan, Dan; Kan, Quancheng

Despite the growing evidence that directly implicates IL-35 for immune evasion of tumor cells due to its inhibitory actions, it is interesting to notice that majority of IL-35 is released from Treg cells. These Treg cells are recruited to tumor sites to avoid any miscalculation, the result of which is less number of CD4 + T cells and CD8 + CTLs in TME to combat cancer. Intriguingly, depletion of Tregs cells exerted similar effects on cancer development as IL-35 when studied alone [80] . Correspondingly, inhibition of mere suppressive signaling from Treg cells devoid of depletion led to better treatment outcomes [81, 82] . Likewise, blockade of Treg cells steered the reversal of CD8+ T cells exhaustion [83] . Increased Treg cells population is also seen in breast cancer patients [66] . Hence it may be plausible to argue that the suppressive action of Treg on T cell growth corresponds with IL-35 actions on the latter. This obviously confirms Treg cells as major producers of IL-35 as manipulation of either of them led to identical findings. Therefore, targeting IL-35 for tumor suppression can also be a viable option. One of the verification is performed by Meghan et al. who introduced EBI3 monoclonal antibody (mAb) that neutralizes IL-35 specifically but does not affect Tregs cells. Study findings manifested that neutralization of IL-35 resulted in improved tumor control in Wild-type C57BL/6 mice as compared to control mice [84] . An unorthodox study in this context is reported by Nicholl MB et al. which although described the role IL-35 in pancreatic cancers but found, rather surprisingly, that it was not expressed by Treg cells but expression found in epithelial derived pancreatic cancer (PCAN) cells [85] . In addition, cytokineinduced killer (CIK) cells are a heterogeneous cells population expressing cell markers for both T cells and natural killer cells and launch a robust attack against cancer cells [86] . CIK have well reported advantages in hematological malignancies and solid tumors in the past [87] [88] [89] . Studies also report the inverse relationship in number and function between Treg cells and CIK, understandably through release of inhibitory cytokines by former [90, 91] . Alternatively it is also documented that dendritic cells co-cultured with CIK led to suppression of Treg cells and its inhibitory cytokines [92] [93] [94] . Interestingly, Ying Pan and colleagues showed that Tregs cells and IL-35 concomitantly increased in a time-dependent manner during the generation of CIK cells as compared to DC-CIK co-cuture, which notably suspended the expression of Treg cells and IL-35 [95] .