Interleukin-27 (IL27) is a cytokine that has significantly different effects on immune responses. IL27 stimulates T cells to promote the secretion of the anti-inflammatory cytokine IL-10, which further helps to reduce inflammatory responses. Together, these properties make IL27 an attractive drug target for the treatment of T cell-mediated inflammatory diseases. IL27 also promotes immune exhaustion by regulating the expression of co-inhibitory receptors.
IL27 expression distribution
IL27 is mainly expressed in monocytes, macrophages, and dendritic cells. In addition, it is also expressed in endothelial cells, perithelial cells, and trophoblast cells.
(Data source: uniprot)
Structure of IL27
IL27 is a heterodimeric cytokine composed of two subunits, EBI3 and p28. The p28 subunit has a four-α-helix bundle structure. When bound to EBI3, the p28 subunit interacts with EBI3 through its four-α-helix bundle domain. They signal through a receptor complex composed of gp130 and IL27Rα (also known as WSX-1 or TCCR), exerting their biological effects by activating the downstream JAK-STAT signaling pathway.
(Data source: Jin Y, et al. EMBO Rep. 2022)
The role of IL27 in immune regulation
IL27 promotes Treg expression of T-bet and CXCR3 and the induction of Tr1 cells, both of which produce IL-10. IL27 has also been associated with increasing the expression of T cell inhibitory receptors, antagonizing the development of Th2 and Th17 cell subsets, and promoting their ability to produce IL-10, a potent antagonist of many dendritic cell functions. IL27 alone has been reported to inhibit the ability of dendritic cells to present antigens and promote their expression of PD-L1.
(Data source Yoshida H, Hunter CA.Annu Rev Immunol. 2015)
The role of IL27 in cancer
Anti-tumor Effects: IL27 may have a direct inhibitory effect on tumor cells expressing the WSX1/gp130 receptor. IL27 promotes anti-tumor immune responses by promoting T-bet expression, supporting Th1 cell differentiation, and enhancing IFN-γ production. IL27 can enhance the activity of cytotoxic T lymphocytes (CTLs), increasing their ability to kill tumor cells. IL27 can directly act on tumor cells, inhibiting their proliferation and survival, invasiveness, and angiogenesis.
Tumor-promoting effects: In certain circumstances, IL27 can induce tumor cells or immune cells in the tumor microenvironment to express immunosuppressive molecules such as PD-L1, IL-10, IDO, and CD39, thereby inhibiting T cell activity and promoting tumor immune escape. IL27 may promote the activity of immunosuppressive cells in the tumor microenvironment (such as Treg cells and myeloid-derived suppressor cells), thereby inhibiting effective anti-tumor immune responses.
(Data source: Fabbi M, et al. Mediators Inflamm. 2017)
IL27 targeted therapeutic drugs
Casdozokitug is a monoclonal antibody targeting IL27 developed by Coherus and is currently in Phase 2 clinical trials. It can inhibit all downstream signals of the JAK-STAT pathway by blocking the interaction between IL27 and its receptor IL27 RA, thereby promoting immune activation in the tumor microenvironment. Casdozokitug has been granted orphan drug designation and fast track designation by the FDA for the treatment of refractory hepatocellular carcinoma. This is the first IL27 antibody to enter the clinic. In clinical trials, blocking IL27 with casdozokitug resulted in monotherapy inhibition of tumor growth and partial remission in patients with non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) (NCT04374877), and ongoing trials are studying its combination with PD-1/PD-L1 pathway blockade for the treatment of NSCLC and hepatocellular carcinoma (HCC).
