Review

Authors: Dario A A Vignali, Vijay K Kuchroo

The interleukin 12 (IL-12) family is unique in having the only heterodimeric cytokines, including IL-12, IL-23, IL-27 and IL-35. This feature endows these cytokines with a unique set of connections and functional interactions not shared by other cytokine families. Despite sharing many structural features and molecular partners, cytokines of the IL-12 family mediate surprisingly diverse functional effects. Here we discuss the unique and unusual structural and functional characteristics of this cytokine family. We outline how cells might interpret seemingly similar cytokine signals to give rise to the diverse functional outcomes that characterize this cytokine family. We also discuss the therapeutic implications of this complexity.

Topics: Humans; Inflammation; Inflammation Mediators; Interleukin-12; Interleukin-17; Interleukin-23; Interleukins; Protein Multimerization; Signal Transduction; T-Lymphocytes

PubMed: 22814351
DOI: 10.1038/ni.2366

Review

Authors: Elia D Tait Wojno, Christopher A Hunter, Jason S Stumhofer...

The discovery of interleukin (IL)-6 and its receptor subunits provided a foundation to understand the biology of a group of related cytokines: IL-12, IL-23, and IL-27. These family members utilize shared receptors and cytokine subunits and influence the outcome of cancer, infection, and inflammatory diseases. Consequently, many facets of their biology are being therapeutically targeted. Here, we review the landmark discoveries in this field, the combinatorial biology inherent to this family, and how patient datasets have underscored the critical role of these pathways in human disease. We present significant knowledge gaps, including how similar signals from these cytokines can mediate distinct outcomes, and discuss how a better understanding of the biology of the IL-12 family provides new therapeutic opportunities.

Topics: Animals; Autoimmune Diseases; Cytokines; Humans; Immunity, Cellular; Inflammation; Interleukin-12; Interleukin-27; Lymphocyte Subsets; Lymphopoiesis; Mice; Mice, Knockout; Multigene Family; Neoplasms, Experimental; Protein Subunits; Structure-Activity Relationship

PubMed: 30995503
DOI: 10.1016/j.immuni.2019.03.011

Review

Authors: Iñigo Terrén, Ane Orrantia, Gabirel Astarloa-Pando...

Natural killer (NK) cells are lymphocytes with a key role in the defense against viral infections and tumor cells. Although NK cells are classified as innate lymphoid cells (ILCs), under certain circumstances they exhibit adaptive and memory-like features. The latter may be achieved, among others, by a brief stimulation with interleukin (IL)-12, IL-15 and IL-18. These cytokine-induced memory-like (CIML) NK cells resemble the trained immunity observed in myeloid cells. CIML NK cells undergo transcriptional, epigenetic and metabolic reprogramming that, along with changes in the expression of cell surface receptors and components of cytotoxic granules, are responsible for their enhanced effector functions after a resting period. In addition, these memory-like NK cells persist for a long time, which make them a good candidate for cancer immunotherapy. Currently, several clinical trials are testing CIML NK cells infusions to treat tumors, mostly hematological malignancies. In relapse/refractory acute myeloid leukemia (AML), the adoptive transfer of CIML NK cells is safe and complete clinical remissions have been observed. In our review, we sought to summarize the current knowledge about the generation and molecular basis of NK cell memory-like responses and the up-to-date results from clinical trials with CIML NK cells.

Topics: Cytokines; Immunity, Innate; Immunologic Memory; Interleukin-12; Killer Cells, Natural

PubMed: 35603208
DOI: 10.3389/fimmu.2022.884648

Review

Authors: Khue G Nguyen, Maura R Vrabel, Siena M Mantooth...

Interleukin-12 (IL-12) is a potent, pro-inflammatory type 1 cytokine that has long been studied as a potential immunotherapy for cancer. Unfortunately, IL-12's remarkable antitumor efficacy in preclinical models has yet to be replicated in humans. Early clinical trials in the mid-1990's showed that systemic delivery of IL-12 incurred dose-limiting toxicities. Nevertheless, IL-12's pleiotropic activity, i.e., its ability to engage multiple effector mechanisms and reverse tumor-induced immunosuppression, continues to entice cancer researchers. The development of strategies which maximize IL-12 delivery to the tumor microenvironment while minimizing systemic exposure are of increasing interest. Diverse IL-12 delivery systems, from immunocytokine fusions to polymeric nanoparticles, have demonstrated robust antitumor immunity with reduced adverse events in preclinical studies. Several localized IL-12 delivery approaches have recently reached the clinical stage with several more at the precipice of translation. Taken together, localized delivery systems are supporting an IL-12 renaissance which may finally allow this potent cytokine to fulfill its considerable clinical potential. This review begins with a brief historical account of cytokine monotherapies and describes how IL-12 went from promising new cure to ostracized black sheep following multiple on-study deaths. The bulk of this comprehensive review focuses on developments in diverse localized delivery strategies for IL-12-based cancer immunotherapies. Advantages and limitations of different delivery technologies are highlighted. Finally, perspectives on how IL-12-based immunotherapies may be utilized for widespread clinical application in the very near future are offered.

Topics: Animals; Antineoplastic Agents; Drug Carriers; Drug Compounding; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Immunotherapy; Interleukin-12; Neoplasms; Treatment Outcome; Tumor Microenvironment

PubMed: 33178203
DOI: 10.3389/fimmu.2020.575597

Authors: Caleb R Glassman, Yamuna Kalyani Mathiharan, Kevin M Jude...

Interleukin-12 (IL-12) and IL-23 are heterodimeric cytokines that are produced by antigen-presenting cells to regulate the activation and differentiation of lymphocytes, and they share IL-12Rβ1 as a receptor signaling subunit. We present a crystal structure of the quaternary IL-23 (IL-23p19/p40)/IL-23R/IL-12Rβ1 complex, together with cryoelectron microscopy (cryo-EM) maps of the complete IL-12 (IL-12p35/p40)/IL-12Rβ2/IL-12Rβ1 and IL-23 receptor (IL-23R) complexes, which reveal "non-canonical" topologies where IL-12Rβ1 directly engages the common p40 subunit. We targeted the shared IL-12Rβ1/p40 interface to design a panel of IL-12 partial agonists that preserved interferon gamma (IFNγ) induction by CD8 T cells but impaired cytokine production from natural killer (NK) cells in vitro. These cell-biased properties were recapitulated in vivo, where IL-12 partial agonists elicited anti-tumor immunity to MC-38 murine adenocarcinoma absent the NK-cell-mediated toxicity seen with wild-type IL-12. Thus, the structural mechanism of receptor sharing used by IL-12 family cytokines provides a protein interface blueprint for tuning this cytokine axis for therapeutics.

Topics: Amino Acid Sequence; Animals; Binding Sites; Cryoelectron Microscopy; Crystallography, X-Ray; Epitopes; Female; HEK293 Cells; Humans; Immunity; Interleukin-12; Interleukin-12 Subunit p40; Killer Cells, Natural; Mice, Inbred C57BL; Models, Molecular; Neoplasms; Protein Structure, Quaternary; Receptors, Interleukin; Receptors, Interleukin-12; Signal Transduction; Structure-Activity Relationship; T-Lymphocytes; Mice

PubMed: 33606986
DOI: 10.1016/j.cell.2021.01.018

Authors: Yingzhong Li, Zhijun Su, Weiyu Zhao...

Therapies that synergistically stimulate immunogenic cancer cell death (ICD), inflammation, and immune priming are of great interest for cancer immunotherapy. However, even multi-agent therapies often fail to trigger all of the steps necessary for self-sustaining anti-tumor immunity. Here we describe self-replicating RNAs encapsulated in lipid nanoparticles (LNP-replicons), which combine three key elements: (1) an LNP composition that potently promotes ICD, (2) RNA that stimulates danger sensors in transfected cells, and (3) RNA-encoded IL-12 for modulation of immune cells. Intratumoral administration of LNP-replicons led to high-level expression of IL-12, stimulation of a type I interferon response, and cancer cell ICD, resulting in a highly inflamed tumor microenvironment and priming of systemic anti-tumor immunity. In several mouse models of cancer, a single intratumoral injection of replicon-LNPs eradicated large established tumors, induced protective immune memory, and enabled regression of distal uninjected tumors. LNP-replicons are thus a promising multifunctional single-agent immunotherapeutic.

Topics: Animals; Immunotherapy; Interleukin-12; Liposomes; Mice; Nanoparticles; Neoplasms; RNA; Tumor Microenvironment

PubMed: 34447945
DOI: 10.1038/s43018-020-0095-6

Authors: Jianfang Ning, Hiroaki Wakimoto, Samuel D Rabkin...

Topics: Animals; Disease Models, Animal; Glioblastoma; Immunotherapy; Interleukin-12; Oncolytic Virotherapy; Simplexvirus

PubMed: 24241205
DOI: 10.4161/cc.27039

Authors: Aslan Mansurov, Peyman Hosseinchi, Kevin Chang...

Immune-checkpoint inhibitors have shown modest efficacy against immunologically 'cold' tumours. Interleukin-12 (IL-12)-a cytokine that promotes the recruitment of immune cells into tumours as well as immune cell activation, also in cold tumours-can cause severe immune-related adverse events in patients. Here, by exploiting the preferential overexpression of proteases in tumours, we show that fusing a domain of the IL-12 receptor to IL-12 via a linker cleavable by tumour-associated proteases largely restricts the pro-inflammatory effects of IL-12 to tumour sites. In mouse models of subcutaneous adenocarcinoma and orthotopic melanoma, masked IL-12 delivered intravenously did not cause systemic IL-12 signalling and eliminated systemic immune-related adverse events, led to potent therapeutic effects via the remodelling of the immune-suppressive microenvironment, and rendered cold tumours responsive to immune-checkpoint inhibition. We also show that masked IL-12 is activated in tumour lysates from patients. Protease-sensitive masking of potent yet toxic cytokines may facilitate their clinical translation.

Topics: Animals; Cytokines; Immunotherapy; Interleukin-12; Melanoma; Mice; Peptide Hydrolases; Tumor Microenvironment

PubMed: 35534574
DOI: 10.1038/s41551-022-00888-0

Review

Authors: Santosh K Katiyar

UV radiation induces immunosuppression and inflammatory responses, as well as oxidative stress and DNA damage, in skin cells and these various effects have been implicated in melanoma and nonmelanoma skin cancers, i.e., photocarcinogenesis. The cytokine interleukin (IL)-12 has been shown to possess potent antitumor activity in a wide variety of murine tumor models. In this review, we summarize the evidence that IL-12 plays a role in preventing photocarcinogenesis, and present a model of its possible mechanisms of action. Treatment of mice with IL-12 prevents UV-induced immunosuppression in a process mediated by repair of UV-induced damaged DNA. After exposure to the photocarcinogenesis protocol, the development of UV-induced tumors is more rapid and the tumor multiplicity and tumor size are significantly greater in IL-12-deficient or knockout (KO) mice than their wild-type counterparts. IL-12-deficiency in mice enhances the proliferation potential of tumor cells, and this may be one of the reasons for the rapid growth of the tumors and their greater size. The rate of malignant transformation of UV-induced papillomas to carcinomas also is higher in the IL-12 KO mice than in their wild-type counterparts in terms of carcinoma incidence and carcinoma multiplicity. UV-induced DNA damage in the form of cyclobutane pyrimidine dimers (CPDs) and sunburn cells is lower, or repaired more rapidly, in wild-type mice than IL-12 KO mice. The IL-12-associated reduction in UV-specific CPDs is due to induction of DNA repair, and particularly enhancement of nucleotide-excision repair. We suggest that endogenous stimulation of IL-12 may protect the skin from UV-induced immunosuppression, DNA damage, and, ultimately, the risk of photocarcinogenesis. Taken together, this information suggests that augmentation of IL-12 should be considered as a strategy for the prevention and treatment of photocarcinogenesis.

Topics: Animals; Cell Proliferation; Humans; Interleukin-12; Models, Biological; Oxidative Stress; Skin Neoplasms; Ultraviolet Rays

PubMed: 17239911
DOI: 10.1016/j.taap.2006.11.017

Review

Authors: Zhezhe Tian, Qiaorui Zhao, Xiu Teng...

IBD (inflammatory bowel disease) is a chronic inflammatory disease of the gastrointestinal tract with increasing incidence worldwide. Multiple factors, such as genetic background, environmental and luminal factors, and mucosal immune dysregulation, have been implicated in the cause of IBD, although the cause of the disease remains unknown. IL-12 and IL-23 and their downstream signaling pathways participate in the pathogenesis of inflammatory bowel disease. Early and aggressive treatment with biologic therapies or novel small molecules is needed to decrease complications and the need for hospitalization and surgery. The landscape of inflammatory bowel disease (IBD) treatment has tremendously improved with the development of biologics and small molecule drugs. Several novel biologics and small molecule drugs targeting IL-12 and IL-23 and their downstream targets have shown positive efficacy and safety data in clinical trials, and several drugs have been approved for the treatment of IBD. In the future, numerous potential emerging therapeutic options for IBD treatment are believed to come to the fore, achieving disease cure.

Topics: Humans; Inflammatory Bowel Diseases; Janus Kinase Inhibitors; Interleukin-23; Interleukin-12; Animals; Signal Transduction

PubMed: 39086483
DOI: 10.3389/fimmu.2024.1393463