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Immunity Apr 2019The 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.... (Review)
Review
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 -
Journal of Controlled Release :... May 2022Cytokines are important immunotherapeutics with approved drugs for the treatment of human cancers. However, systemic administration of cytokines often fails to achieve...
Cytokines are important immunotherapeutics with approved drugs for the treatment of human cancers. However, systemic administration of cytokines often fails to achieve adequate concentrations to immune cells in tumors due to dose-limiting toxicity. Thus, developing localized therapy that directly delivers immune-stimulatory cytokines to tumors may improve the therapeutic efficacy. In this study, we generated novel lipid nanoparticles (LNPs) encapsulated with mRNAs encoding cytokines including IL-12, IL-27 and GM-CSF, and tested their anti-tumor activity. We first synthesized ionizable lipid materials containing di-amino groups with various head groups (DALs). The novel DAL4-LNP effectively delivered different mRNAs in vitro to tumor cells and in vivo to tumors. Intratumoral injection of DAL4-LNP loaded with IL-12 mRNA was most potent in inhibiting B16F10 melanoma tumor growth compared to IL-27 or GM-CSF mRNAs in monotherapy. Furthermore, intratumoral injection of dual DAL4-LNP-IL-12 mRNA and IL-27 mRNA showed a synergistic effect in suppressing tumor growth without causing systematic toxicity. Most importantly, intratumoral delivery of IL-12 and IL-27 mRNAs induced robust infiltration of immune effector cells, including IFN-γ and TNF-α producing NK and CD8 T cells into tumors. Thus, intratumoral administration of DAL-LNP loaded with IL-12 and IL-27 mRNA provides a new treatment strategy for cancer.
Topics: CD8-Positive T-Lymphocytes; Cytokines; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunotherapy; Interleukin-12; Interleukin-27; Liposomes; Nanoparticles; Neoplasms; RNA, Messenger
PubMed: 35301053
DOI: 10.1016/j.jconrel.2022.03.021 -
Frontiers in Immunology 2022Natural 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... (Review)
Review
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 -
American Journal of Clinical Dermatology Jan 2022Generalized pustular psoriasis (GPP) is a rare, severe neutrophilic skin disorder characterized by sudden widespread eruption of superficial sterile pustules with or... (Review)
Review
Generalized pustular psoriasis (GPP) is a rare, severe neutrophilic skin disorder characterized by sudden widespread eruption of superficial sterile pustules with or without systemic inflammation. GPP flares can be life-threatening if untreated due to potential severe complications such as cardiovascular failure and serious infections. Currently, there are no GPP-specific therapies approved in the USA or Europe. Retinoids, cyclosporine, and methotrexate are the most commonly used non-biologic therapies for GPP. The evidence that supports the currently available treatment options is mainly based on case reports and small, open-label, single-arm studies. However, recent advances in our understanding of the pathogenic mechanisms of GPP and the identification of gene mutations linked to the disease have paved the way for the development of specific targeted therapies that selectively suppress the autoinflammatory and autoimmune mechanisms induced during GPP flares. Several biologic agents that target key cytokines involved in the activation of inflammatory pathways, such as tumor necrosis factor-α blockers and interleukin (IL)-17, IL-23, and IL-12 inhibitors, have emerged as potential treatments for GPP, with several being approved in Japan. The evidence supporting the efficacy of these agents is mainly derived from small, uncontrolled trials. A notable recent advance is the discovery of IL36RN mutations and the central role of IL-36 receptor ligands in the pathogenesis of GPP, which has defined key therapeutic targets for the disease. Biologic agents that target the IL-36 pathway have demonstrated promising efficacy in patients with GPP, marking the beginning of a new era of targeted therapy for GPP.
Topics: Biological Products; Humans; Interleukin-12; Interleukin-17; Interleukin-23; Interleukins; Psoriasis; Skin Diseases, Vesiculobullous
PubMed: 35061230
DOI: 10.1007/s40257-021-00658-9 -
Frontiers in Immunology 2020Interleukin-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... (Review)
Review
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 -
Immunity Dec 2018Anti-PD-1 immune checkpoint blockers can induce sustained clinical responses in cancer but how they function in vivo remains incompletely understood. Here, we combined...
Anti-PD-1 immune checkpoint blockers can induce sustained clinical responses in cancer but how they function in vivo remains incompletely understood. Here, we combined intravital real-time imaging with single-cell RNA sequencing analysis and mouse models to uncover anti-PD-1 pharmacodynamics directly within tumors. We showed that effective antitumor responses required a subset of tumor-infiltrating dendritic cells (DCs), which produced interleukin 12 (IL-12). These DCs did not bind anti-PD-1 but produced IL-12 upon sensing interferon γ (IFN-γ) that was released from neighboring T cells. In turn, DC-derived IL-12 stimulated antitumor T cell immunity. These findings suggest that full-fledged activation of antitumor T cells by anti-PD-1 is not direct, but rather involves T cell:DC crosstalk and is licensed by IFN-γ and IL-12. Furthermore, we found that activating the non-canonical NF-κB transcription factor pathway amplified IL-12-producing DCs and sensitized tumors to anti-PD-1 treatment, suggesting a therapeutic strategy to improve responses to checkpoint blockade.
Topics: Adult; Aged; Aged, 80 and over; Animals; Antibodies, Monoclonal; Dendritic Cells; Female; Humans; Immunotherapy; Interferon-gamma; Interleukin-12; Male; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; NF-kappa B; Neoplasms; Programmed Cell Death 1 Receptor; Signal Transduction; T-Lymphocytes
PubMed: 30552023
DOI: 10.1016/j.immuni.2018.09.024 -
Cell Feb 2021Interleukin-12 (IL-12) and IL-23 are heterodimeric cytokines that are produced by antigen-presenting cells to regulate the activation and differentiation of lymphocytes,...
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 -
Cell Apr 2021Metastasis is the leading cause of cancer-related deaths, and greater knowledge of the metastatic microenvironment is necessary to effectively target this process....
Metastasis is the leading cause of cancer-related deaths, and greater knowledge of the metastatic microenvironment is necessary to effectively target this process. Microenvironmental changes occur at distant sites prior to clinically detectable metastatic disease; however, the key niche regulatory signals during metastatic progression remain poorly characterized. Here, we identify a core immune suppression gene signature in pre-metastatic niche formation that is expressed predominantly by myeloid cells. We target this immune suppression program by utilizing genetically engineered myeloid cells (GEMys) to deliver IL-12 to modulate the metastatic microenvironment. Our data demonstrate that IL12-GEMy treatment reverses immune suppression in the pre-metastatic niche by activating antigen presentation and T cell activation, resulting in reduced metastatic and primary tumor burden and improved survival of tumor-bearing mice. We demonstrate that IL12-GEMys can functionally modulate the core program of immune suppression in the pre-metastatic niche to successfully rebalance the dysregulated metastatic microenvironment in cancer.
Topics: Adaptive Immunity; Animals; Cell Line, Tumor; Genetic Engineering; Humans; Immunosuppression Therapy; Interleukin-12; Lung; Lung Neoplasms; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myeloid Cells; Neoplasm Metastasis; Rhabdomyosarcoma; Survival Rate; T-Lymphocytes; Tumor Microenvironment
PubMed: 33765443
DOI: 10.1016/j.cell.2021.02.048 -
Science Immunology Jan 2022It is a challenge to effectively reactivate preexisting tumor-infiltrating lymphocytes (TILs) without causing severe toxicity. Interleukin-12 (IL-12) can potently...
It is a challenge to effectively reactivate preexisting tumor-infiltrating lymphocytes (TILs) without causing severe toxicity. Interleukin-12 (IL-12) can potently activate lymphocytes, but its clinical use is limited by its short half-life and dose-related toxicity. In this study, we developed a tumor-conditional IL-12 (pro-IL-12), which masked IL-12 with selective extracellular receptor–binding domains of the IL-12 receptor while preferentially and persistently activating TILs after being unmasked by matrix metalloproteinases expressed by tumors. Systemic delivery of pro-IL-12 demonstrated reduced toxicity but better control of established tumors compared with IL-12-Fc. Mechanistically, antitumor responses induced by pro-IL-12 were dependent on TILs and IFNγ. Furthermore, direct binding of IL-12 to IL-12R on CD8, not CD4, T cells was essential for maximal effectiveness. Pro-IL-12 improved the efficacy of both immune checkpoint blockade and targeted therapy when used in combination. Therefore, our study demonstrated that pro-IL-12 could rejuvenate TILs, which then combined with current treatment modalities while limiting adverse effects for treating established tumors.
Topics: Animals; Female; Interleukin-12; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Neoplasms; T-Lymphocytes, Cytotoxic
PubMed: 34995098
DOI: 10.1126/sciimmunol.abi6899 -
ELife Aug 2022Dendritic cells (DCs) play an important role in anti-tumor immunity by inducing T cell differentiation. Herein, we found that the DC mechanical sensor Piezo1 stimulated...
Dendritic cells (DCs) play an important role in anti-tumor immunity by inducing T cell differentiation. Herein, we found that the DC mechanical sensor Piezo1 stimulated by mechanical stiffness or inflammatory signals directs the reciprocal differentiation of T1 and regulatory T (T) cells in cancer. Genetic deletion of Piezo1 in DCs inhibited the generation of T1 cells while driving the development of T cells in promoting cancer growth in mice. Mechanistically, Piezo1-deficient DCs regulated the secretion of the polarizing cytokines TGFβ1 and IL-12, leading to increased TGFβR2-p-Smad3 activity and decreased IL-12Rβ2-p-STAT4 activity while inducing the reciprocal differentiation of T and T1 cells. In addition, Piezo1 integrated the SIRT1-hypoxia-inducible factor-1 alpha (HIF1α)-dependent metabolic pathway and calcium-calcineurin-NFAT signaling pathway to orchestrate reciprocal T1 and T lineage commitment through DC-derived IL-12 and TGFβ1. Our studies provide critical insight for understanding the role of the DC-based mechanical regulation of immunopathology in directing T cell lineage commitment in tumor microenvironments.
Topics: Animals; Cell Differentiation; Dendritic Cells; Interleukin-12; Ion Channels; Mice; Neoplasms; T-Lymphocytes, Regulatory; Th1 Cells; Th17 Cells; Th2 Cells; Tumor Microenvironment
PubMed: 35993548
DOI: 10.7554/eLife.79957