Targeting STING to promote antitumor immunity Chin, Emily N.; Sulpizio, Ariana; Lairson, Luke L.
Trends in cell biology,
March 2023, 2023-03-00, Letnik:
33, Številka:
3
Journal Article
Recenzirano
Pharmacology-based methods that promote antitumor immunity have the potential to be highly efficacious while avoiding the systemic cytotoxicity associated with traditional chemotherapies. Activation ...of type I interferon (IFN) signaling in antigen-presenting cell types e.g., macrophages and dendritic cells (DCs) is critical, if not essential, for inducing a tumor-specific adaptive immune response, including the activation of cytolytic CD8 T cells. In the context of promoting antitumor immunity, the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway has emerged as a principal regulator of essential type I IFN signaling. As such, STING represents a highly attractive target for developing a first-in-class immunotherapy, albeit one with a potential for significant cell type- and downstream pathway-dependent on-target toxicities, as well as conceivable pharmacogenomic liabilities.
Synthetic cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) agonists have significant potential as antitumor agents, based on their ability to stimulate type I interferon-dependent activation of cytolytic CD8 T cells and nuclear factor kappa B (NF-κB) pathway-mediated tumor hemorrhagic necrosis.Recent mechanistic work has revealed that activation of interferon regulatory factor 3 (IRF3) and NF-κB by STING, as well as the associated antitumor effects, can diverge in a cell type-dependent manner.Non-nucleotide synthetic STING agonists that induce ‘open’ or ‘closed’ STING dimer conformations have recently been identified and were demonstrated to elicit robust antitumor effects following systemic administration in rodent models.Narrow therapeutic indices and perceivable pharmacogenomic liabilities represent potential impediments to the clinical translation of STING agonists.
Magmatism on Earth is most abundantly expressed by surface volcanic activity, but all volcanism has roots deep in the crust, lithosphere, and mantle. Intraplate magmatism, in particular, has remained ...enigmatic as the plate tectonic paradigm cannot easily explain phenomena such as large flood basalt provinces and lithospheric rupture within continental interiors. Here, I explore the role of deep crustal magmatic processes and their connection to continental rift volcanism as recorded in deep crustal xenoliths from northern Tanzania. The xenoliths are interpreted as magmatic cumulates related to Cenozoic rift volcanism, based on their undeformed, cumulate textures and whole-rock compositions distinct from melt-reacted peridotites. The cumulates define linear trends in terms of whole-rock major elements and mineralogically, can be represented as mixtures of olivine + clinopyroxene. AlphaMELTS modeling of geologically plausible parental melts shows that the end-member cumulates, clinopyroxenite and Fe-rich dunite, require fractionation from two distinct melts: a strongly diopside-normative melt and a fractionated picritic melt, respectively. The former can be linked to the earliest, strongly silica-undersaturated rift lavas sourced from melting of metasomatized lithosphere, whereas the latter is linked to the increasing contribution from the upwelling asthenospheric plume beneath East Africa. Thus, deep crustal cumulate systematics reflect temporal and compositional trends in rift volcanism, and show that mixing, required by the geochemistry of many rift lava suites, is also mirrored in the lavas’ cumulates.
In Tanzania, the deep lithospheric mantle (> 70 km depth) is characterized by significantly higher electrical conductivity within the cratonic root than in the Mozambique belt. Such contrasts are ...typically attributed to changes in volatiles and/or melt content, with changes in mineralogy deemed insufficient to impact conductivity. To test this assumption, electrical conductivity measurements were conducted at pressure-temperature conditions relevant to the Tanzanian lithosphere (1.5 and 3 GPa; from 400 to >1500 °C) on dunite (depleted) and pyroxenite (fertile) xenoliths from Engorora, Northern Tanzania. Once garnet becomes stable in the fertile mantle rock (> 60 km, 1.7 GPa), it nucleates at grain boundaries, forming the backbone of a conductive network. At 3 GPa, such garnet-rich networks increase conductivity by a factor of 100 regardless of temperature. Numerical models demonstrate that the observed low (< 10−2 S⋅m−1) and high (> 10−1 S⋅m−1) conductivity values can be explained by low and high degrees of garnet connectivity, respectively. Such high electrical conductivities in cratonic roots can be explained by the presence of connected garnet clusters or garnet pyroxenites, suggesting mantle fertilization. This new source for electromagnetic signal generation at appropriate pressures and temperatures must be factored in where interpreting magnetotelluric signals at relevant depths in the lithosphere.
Arc magmas are important building blocks of the continental crust. Because many arc lavas are oxidized, continent formation is thought to be associated with oxidizing conditions. On the basis of ...copper's (Cu's) affinity for reduced sulfur phases, we tracked the redox state of arc magmas from mantle source to emplacement in the crust. Primary arc and mid-ocean ridge basalts have identical Cu contents, indicating that the redox states of primitive arc magmas are indistinguishable from that of mid-ocean ridge basalts. During magmatic differentiation, the Cu content of most arc magmas decreases markedly because of sulfide segregation. Because a similar depletion in Cu characterizes global continental crust, the formation of sulfide-bearing cumulates under reducing conditions may be a critical step in continent formation.
Mechanisms that integrate the metabolic state of a cell with regulatory pathways are necessary to maintain cellular homeostasis. Endogenous, intrinsically reactive metabolites can form functional, ...covalent modifications on proteins without the aid of enzymes
, and regulate cellular functions such as metabolism
and transcription
. An important 'sensor' protein that captures specific metabolic information and transforms it into an appropriate response is KEAP1, which contains reactive cysteine residues that collectively act as an electrophile sensor tuned to respond to reactive species resulting from endogenous and xenobiotic molecules. Covalent modification of KEAP1 results in reduced ubiquitination and the accumulation of NRF2
, which then initiates the transcription of cytoprotective genes at antioxidant-response element loci. Here we identify a small-molecule inhibitor of the glycolytic enzyme PGK1, and reveal a direct link between glycolysis and NRF2 signalling. Inhibition of PGK1 results in accumulation of the reactive metabolite methylglyoxal, which selectively modifies KEAP1 to form a methylimidazole crosslink between proximal cysteine and arginine residues (MICA). This posttranslational modification results in the dimerization of KEAP1, the accumulation of NRF2 and activation of the NRF2 transcriptional program. These results demonstrate the existence of direct inter-pathway communication between glycolysis and the KEAP1-NRF2 transcriptional axis, provide insight into the metabolic regulation of the cellular stress response, and suggest a therapeutic strategy for controlling the cytoprotective antioxidant response in several human diseases.
Stimulator of interferon genes (STING) links innate immunity to biological processes ranging from antitumor immunity to microbiome homeostasis. Mechanistic understanding of the anticancer potential ...for STING receptor activation is currently limited by metabolic instability of the natural cyclic dinucleotide (CDN) ligands. From a pathway-targeted cell-based screen, we identified a non-nucleotide, small-molecule STING agonist, termed SR-717, that demonstrates broad interspecies and interallelic specificity. A 1.8-angstrom cocrystal structure revealed that SR-717 functions as a direct cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) mimetic that induces the same "closed" conformation of STING. SR-717 displayed antitumor activity; promoted the activation of CD8
T, natural killer, and dendritic cells in relevant tissues; and facilitated antigen cross-priming. SR-717 also induced the expression of clinically relevant targets, including programmed cell death 1 ligand 1 (PD-L1), in a STING-dependent manner.
High‐elevation, low‐relief continental plateaus are major topographic features and profoundly influence atmospheric circulation, sediment transport and storage, and biodiversity. Although orogenic ...surface‐uplift mechanisms for modern continental plateaus near known plate margins like Tibet are well‐characterized, they cannot account for examples in intracontinental settings like the Colorado Plateau. In contrast to canonical plate‐tectonic uplift mechanisms, broad‐scale hydration‐induced metasomatism of the lower crust has been suggested to reduce its density and increase its buoyancy sufficiently to contribute to isostatic uplift. However, the relationships between key petrophysical properties in these environments are not fully quantified, which limits application of this model. Here, we develop a series of petrological models that describe the petrological and topographic effects of fluid–rock interaction in non‐deforming continental crust of varying composition. We apply an open‐system petrological modelling framework that utilizes reactive‐transport calculations to determine the spatial and temporal scales over which mineralogic transformations take place compared with the magnitude of infiltration of aqueous fluids derived from devolatilization of subducting oceanic lithosphere. The buoyancy effect of hydration‐induced de‐densification is most significant for metabasic lower crust, intermediate for metapelitic crust, and minimal for granodioritic crust. We apply these results to a case study of the ~2 km‐high Colorado Plateau and demonstrate that under ideal conditions, hydration of its lower–middle crust by infiltrating aqueous fluids released by the Farallon slab during Cenozoic low‐angle subduction could have uplifted the plateau surface by a maximum of ~1 km over 16 Myr. However, realistically, although hydration likely has a measurable effect on surface tectonics, the uplift of orogenic plateaus is likely dominantly controlled by other factors, such as lithospheric delamination.
Electrophilic compounds originating from nature or chemical synthesis have profound effects on immune cells. These compounds are thought to act by cysteine modification to alter the functions of ...immune-relevant proteins; however, our understanding of electrophile-sensitive cysteines in the human immune proteome remains limited. Here, we present a global map of cysteines in primary human T cells that are susceptible to covalent modification by electrophilic small molecules. More than 3,000 covalently liganded cysteines were found on functionally and structurally diverse proteins, including many that play fundamental roles in immunology. We further show that electrophilic compounds can impair T cell activation by distinct mechanisms involving the direct functional perturbation and/or degradation of proteins. Our findings reveal a rich content of ligandable cysteines in human T cells and point to electrophilic small molecules as a fertile source for chemical probes and ultimately therapeutics that modulate immunological processes and their associated disorders.
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•Chemical proteomics identifies cysteine reactivity changes in activated T cells•Chemical proteomics maps ligandable cysteines in diverse immune-relevant proteins•Cysteine-directed electrophilic compounds suppress T cells by distinct mechanisms•Electrophile-cysteine interactions promote the degradation of immune proteins
Integrated chemical proteomics and phenotypic screening furnishes a global portrait of cysteine reactivity and ligandability in primary human T cells and enables the discovery of electrophilic small molecules that suppress T cell activation and promote the degradation of immunomodulatory proteins.
Great efforts have been made to increase accessibility of HIV antiretroviral therapy (ART) in low and middle-income countries. The threat of wide-scale emergence of drug resistance could severely ...hamper ART scale-up efforts. Population-based surveillance of transmitted HIV drug resistance ensures the use of appropriate first-line regimens to maximize efficacy of ART programs where drug options are limited. However, traditional HIV genotyping is extremely expensive, providing a cost barrier to wide-scale and frequent HIV drug resistance surveillance.
We have developed a low-cost laboratory-scale next-generation sequencing-based genotyping method to monitor drug resistance. We designed primers specifically to amplify protease and reverse transcriptase from Brazilian HIV subtypes and developed a multiplexing scheme using multiplex identifier tags to minimize cost while providing more robust data than traditional genotyping techniques. Using this approach, we characterized drug resistance from plasma in 81 HIV infected individuals collected in São Paulo, Brazil. We describe the complexities of analyzing next-generation sequencing data and present a simplified open-source workflow to analyze drug resistance data. From this data, we identified drug resistance mutations in 20% of treatment naïve individuals in our cohort, which is similar to frequencies identified using traditional genotyping in Brazilian patient samples.
The developed ultra-wide sequencing approach described here allows multiplexing of at least 48 patient samples per sequencing run, 4 times more than the current genotyping method. This method is also 4-fold more sensitive (5% minimal detection frequency vs. 20%) at a cost 3-5× less than the traditional Sanger-based genotyping method. Lastly, by using a benchtop next-generation sequencer (Roche/454 GS Junior), this approach can be more easily implemented in low-resource settings. This data provides proof-of-concept that next-generation HIV drug resistance genotyping is a feasible and low-cost alternative to current genotyping methods and may be particularly beneficial for in-country surveillance of transmitted drug resistance.
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