Dual Roles of IL-27 in Cancer Biology and Immunotherapy

Abstract

IL-27 is a pleiotropic two-chain cytokine, composed of EBI3 and IL-27p28 subunits, which is structurally related to both IL-12 and IL-6 cytokine families. IL-27 acts through a heterodimer receptor consisting of IL-27Rα (WSX1) and gp130 chains, which mediate signaling predominantly through STAT1 and STAT3. IL-27 was initially reported as an immune-enhancing cytokine that supports CD4+ T cell proliferation, T helper (Th)1 cell differentiation, and IFN-γ production, acting in concert with IL-12. However, subsequent studies demonstrated that IL-27 displays complex immune-regulatory functions, which may result in either proinflammatory or anti-inflammatory effects in relationship to the biological context and experimental models considered. Several pieces of evidence, obtained in preclinical tumor models, indicated that IL-27 has a potent antitumor activity, related not only to the induction of tumor-specific Th1 and cytotoxic T lymphocyte (CTL) responses but also to direct inhibitory effects on tumor cell proliferation, survival, invasiveness, and angiogenic potential. Nonetheless, given its immune-regulatory functions, the effects of IL-27 on cancer may be dual and protumor effects may also occur. Here, we will summarize IL-27 biological activities and its functional overlaps with the IFNs and discuss its dual role in tumors in the light of potential applications to cancer immunotherapy.

The PD-L1- and IL6-mediated dampening of the IL27/STAT1 anticancer responses are prevented by α-PD-L1 or α-IL6 antibodies

“…Also the antitumor effects of other cytokines such as IL12 have been attributed to expression of IFN‐γ . IL27 has been described to have pro‐ or anti‐inflammatory functions in different systems and it is capable of exerting antitumor effects. IL27 seems to be better tolerated than interferons and IL12 in preclinical models, probably because less IFN‐γ is released by IL27 compared to IL12.…”

“…IL27 is involved in T H 1 commitment by suppressing GATA3 (GATA binding protein 3), inducing T‐bet, resulting in IL‐12Rβ2 expression in naïve T cells, thereby supporting the IL12‐dependent IFN‐γ secretion . It activates CD8 + cells, NK cells, induces T H 1 responses and acts on endothelial cells to secrete anti‐angiogenic factors, as does IFN‐γ . IL27 also induced antibody‐dependent cell‐mediated cytotoxicity (ADCC) .…”

“…IL27 does, however, not only act on immune cells but can also elicit antitumor responses in cancer cells directly, such as antiproliferative, pro‐apoptotic, anti‐angiogenic, and anti‐metastatic functions, which have recently been reviewed extensively . Briefly, IL27 showed antiproliferative effects on various melanoma cell lines and, like IFN‐γ, inhibition of angiogenesis .…”

TH17 responses in cytokine storm of COVID-19: An emerging target of JAK2 inhibitor Fedratinib

“…STAT3, a transcription factor mediates IL-6 and IL-23 signals for TH17 cell initial differentiation and effector function. Both IL-6 and IL-23 activate STAT3 through JAK2 (IL-6 also use JAK1) 9 , whereas IL-21 activates STAT3 (and STAT1 and STAT5) through JAK1 and JAK3. We postulate that JAK2 inhibitors can be used to restrict the proinflammatory function of existing TH17 cells.…”

IL-27 mediates HLA class I up-regulation, which can be inhibited by the IL-6 pathway, in HLA-deficient Small Cell Lung Cancer cells

“…On the other hand, IL-27 induces the expression of immune-regulatory molecules such as the IL-18 natural inhibitor, IL-18BP [26], the tryptophan catabolic enzyme IDO and PD-L1 [27], in neoplastic cells. Therefore, IL-27 may have a dual role in anti-tumor immunity [28] and shares several immune-regulatory functions with IFN-γ, in relationship to the common usage of the STAT1 intracellular signaling pathway [18, 19, 23, 29]. …”