Abstract
Simple SummaryThe IL-12 family cytokines play an important role in regulating the tumor immune contexture. Recent efforts geared towards the development of better immune therapeutic approaches have identified the need to overcome immune suppression and improve the quantity and quality of anti-tumor effector immune cells within the tumor milieu. In this review, we summarize the recent findings on IL-12 family cytokines in regulating anti-tumor immunity as well as the effectiveness and benefits of enhancing anti-tumor immunity in pre-clinical and clinical settings by targeting IL-12 family cytokines.The IL-12 family cytokines are a group of unique heterodimeric cytokines that include IL-12, IL-23, IL-27, IL-35 and, most recently, IL-39. Recent studies have solidified the importance of IL-12 cytokines in shaping innate and adaptive immune responses in cancer and identified multipronged roles for distinct IL-12 family members, ranging from effector to regulatory immune functions. These cytokines could serve as promising candidates for the development of immunomodulatory therapeutic approaches. Overall, IL-12 can be considered an effector cytokine and has been found to engage anti-tumor immunity by activating the effector Th1 response, which is required for the activation of cytotoxic T and NK cells and tumor clearance. IL-23 and IL-27 play dual roles in tumor immunity, as they can both activate effector immune responses and promote tumor growth by favoring immune suppression. IL-35 is a potent regulatory cytokine and plays a largely pro-tumorigenic role by inhibiting effector T cells. In this review, we summarize the recent findings on IL-12 family cytokines in the control of tumor growth with an emphasis primarily on immune regulation. We underscore the clinical implications for the use of these cytokines either in the setting of monotherapy or in combination with other conventional therapies for the more effective treatment of malignancies.
Highlights
IL-12 Family Cytokines: Composition, Signaling and Mechanism of ActionThe IL-12 family cytokines are known to play essential roles in regulating innate and adaptive immune responses [1]
IL-12 family cytokines are typically secreted by innate immune cells but can be secreted by adaptive immune cells depending on the disease and immune contexture
31 high-grade glioma patients were treated with human IL-12 vector (Ad-RTS-hIL-12) in a multicenter phase 1 dose-escalation trial (NCT02026271), and showed evidence of increased IFN-γ and PD-1+ tumor-infiltrating lymphocytes [32]. These findings suggest that increases in the concentration of intra-tumoral IL-12 improve the efficacy of adoptive T cell therapies
Summary
The IL-12 family cytokines are known to play essential roles in regulating innate and adaptive immune responses [1]. Similar preclinical studies in a hepatocellular carcinoma model indicated that IL-12-expressing CAR T cells produced high levels of effector cytokines, accompanied by attenuated Treg cell infiltration and induced tumor cell lysis [35]. These observations reveal that the inducible expression of IL-12 improves the anti-tumor functions of CAR T cells and might provide a promising treatment strategy for cancer patients (Figure 2). Combined immune therapy with IL-12 and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in humanized mouse models of hepatocellular carcinoma increased the infiltration of IFN-γ-producing NK cells and promoted the apoptosis of cancer cells. We discuss the dual role of IL-23 in modulating effector and/or regulatory immune responses in cancer
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