IL15 and IL21: Better When Membrane-Tethered Together on Antitumor T Cells.

Systemic administration of homeostatic γ-chain cytokines mediates antitumor responses in some patients treated with adoptive immunotherapy. Yet many patients experience toxic side effects. New work presented herein suggests these limitations can be overcome by membrane-tethering IL15 and IL21 to T-cell products. This finding has major implications in advancing medicine. See related article by Nguyen et al., p. 1555.

Distinct host preconditioning regimens differentially impact the antitumor potency of adoptively transferred Th17 cells.

Background: Mechanisms by which distinct methods of host preconditioning impact the efficacy of adoptively transferred antitumor T helper cells is unknown. Methods: CD4 + T cells with a transgenic TCR that recognize TRP-1 melanoma antigen were polarized to the T helper 17 (Th17) phenotype and then transferred into melanoma-bearing mice preconditioned with either total body irradiation or chemotherapy. Results: We found that preconditioning mice with a non-myeloablative dose of total body irradiation (TBI of 5 Gy) was more effective than using an equivalently dosed non-myeloablative chemotherapy (CTX at 200 mg/kg) at augmenting therapeutic activity of anti-tumor TRP-1 Th17 cells. Anti-tumor Th17 cells engrafted better following preconditioning with TBI and regressed large established melanoma in all animals. Conversely, only half of mice survived long-term when preconditioned with CTX and infused with anti-melanoma Th17 cells. IL-17 and IFN-g produced by the infused Th17 cells, were detected in animals given either TBI or CTX preconditioning. Interestingly, inflammatory cytokines (G-CSF, IL-6, MCP-1, IL-5, and KC) were significantly elevated in the serum of mice preconditioned with TBI versus CTX after Th17 therapy. Conclusions: Our results indicate, for the first time, that the antitumor response, persistence, and cytokine profiles resulting from Th17 therapy are impacted by the specific regimen of host preconditioning. This work is important for understanding mechanisms that promote long-lived responses by ACT, particularly as CD4 + based T cell therapies are now emerging in the clinic.

Shared and Unique Features of Human Interferon-Beta and Interferon-Alpha Subtypes.

Type I interferons (IFN-I) were first discovered as an antiviral factor by Isaacs and Lindenmann in 1957, but they are now known to also modulate innate and adaptive immunity and suppress proliferation of cancer cells. While much has been revealed about IFN-I, it remains a mystery as to why there are 16 different IFN-I gene products, including IFNß, IFNω, and 12 subtypes of IFNα. Here, we discuss shared and unique aspects of these IFN-I in the context of their evolution, expression patterns, and signaling through their shared heterodimeric receptor. We propose that rather than investigating responses to individual IFN-I, these contexts can serve as an alternative approach toward investigating roles for IFNα subtypes. Finally, we review uses of IFNα and IFNß as therapeutic agents to suppress chronic viral infections or to treat multiple sclerosis.

S27 of IFNα1 Contributes to Its Low Affinity for IFNAR2 and Weak Antiviral Activity.

Type I interferons (IFNs) signal by forming a high affinity IFN-IFNAR2 dimer, which subsequently recruits IFNAR1 to form a ternary complex that initiates JAK/STAT signaling. Among the 12 IFNα subtypes, IFNα1 has a uniquely low affinity for IFNAR2 (<100 × of the other IFNα subtypes) and commensurately weak antiviral activity, suggesting an undefined function distinct from suppression of viral infections. Also unique in IFNα1 is substitution of a serine for phenylalanine at position 27, a contact point that stabilizes the IFNα:IFNAR2 hydrophobic interface. To determine whether IFNα1-S27 contributes to the low affinity for IFNAR2, we created an IFNα1 mutein, IFNα1-S27F, and compared it to wild-type IFNα1 and IFNα2. Substitution of phenylalanine for serine increased affinity for IFNAR2 ∼4-fold and commensurately enhanced activation of STAT1, STAT3, and STAT5, transcription of a subset of interferon stimulated genes, and restriction of vesicular stomatitis virus infection in vitro. Structural modeling suggests that S27 of IFNα1 disrupts the IFNα:IFNAR2 hydrophobic interface that is otherwise stabilized by F27 and that replacing S27 with phenylalanine partially restores the hydrophobic surface. Disruption of the hydrophobic IFNα:IFNAR2 interface by the unique S27 of IFN α1 contributes to its low affinity and weak antiviral activity.

MMP14 Regulates Cranial Neural Crest Epithelial-to-Mesenchymal Transition and Migration.

BACKGROUND: Neural crest is a vertebrate specific cell population. Induced at lateral borders of the neural plate, neural crest cells (NCCs) subsequently undergo epithelial-to-mesenchymal transition (EMT) to detach from the neuroepithelium before migrating into various locations in the embryo. Despite the wealth of knowledge of transcription factors involved in this process, little is known about the effectors that directly regulate neural crest EMT and migration. RESULTS: Here, we examined the activity of matrix metalloproteinase MMP14 in NCCs and found that MMP14 is expressed in both premigratory and migrating NCCs. Overexpression of MMP14 led to premature migration of NCCs, while down-regulation of MMP14 resulted in reduced neural crest migration. Transplantation experiment further showed that MMP14 is required in NCCs, whereas MMP2, which can be activated by MMP14, is required in the surrounding mesenchyme. in vitro explant culture showed that MMP14 is required for neural crest EMT but not for spreading. This is possibly mediated by the changes in cadherin levels, as decreasing MMP14 level led to increased cadherin expression and increasing MMP14 level led to reduced cadherin expression. CONCLUSIONS: The results demonstrate that MMP14 is critical for neural crest EMT and migration, partially through regulating the levels of cadherins. Developmental Dynamics 247:1083-1092, 2018. © 2018 Wiley Periodicals, Inc.