Search

Antigen processing is an immunological mechanism by which intracellular peptides are transported to the cell surface while bound to Major Histocompatibility Complex molecules, where they can be surveyed by circulating CD8+ or CD4+ T-cells, potentially triggering an immunological response. The antigen processing pathway is a complex multistage filter that refines a huge pool of potential peptide ligands derived from protein degradation into a smaller ensemble for surface presentation. Each stage presents unique challenges due to the number of ligands, the polymorphic nature of MHC and other protein constituents of the pathway and the nature of the interactions between them. Predicting the ensemble of displayed peptide antigens, as well as their immunogenicity, is critical for improving T cell vaccines against pathogens and cancer. Our predictive abilities have always been hindered by an incomplete empirical understanding of the antigen processing pathway. In this review, we highlight the role of computational and structural approaches in improving our understanding of antigen processing, including structural biology, computer simulation, and machine learning techniques, with a particular focus on the MHC-I pathway.

Oesophageal adenocarcinoma (OAC) has a relatively poor long-term survival and limited treatment options. Promising targets for immunotherapy are short peptide neoantigens containing tumour mutations, presented to cytotoxic T-cells by human leucocyte antigen (HLA) molecules. Despite an association between putative neoantigen abundance and therapeutic response across cancers, immunogenic neoantigens are challenging to identify. Here we characterized the mutational and immunopeptidomic landscapes of tumours from a cohort of seven patients with OAC. We directly identified one HLA-I presented neoantigen from one patient, and report functional T-cell responses from a predicted HLA-II neoantigen in a second patient. The predicted class II neoantigen contains both HLA I and II binding motifs. Our exploratory observations are consistent with previous neoantigen studies in finding that neoantigens are rarely directly observed, and an identification success rate following prediction in the order of 10%. However, our identified putative neoantigen is capable of eliciting strong T-cell responses, emphasizing the need for improved strategies for neoantigen identification.

Erg Chech (EC) 002 is a meteorite with andesitic composition, potentially recording the lava crystallization and crust formation of its parent body. Nucleosynthetic Cr isotope composition (ε54Cr = −0.35 ± 0.06) for EC 002 suggests a non-carbonaceous region of the Solar system, and possibly represents the crustal composition of the brachinite parent body. The 53Mn-to-53Cr decay system shows it crystallized at 4566.6 ± 0.6 Ma, i.e. 0.7 ± 0.6 Ma after Solar system formation (only considering the cogenetic matrix fractions with similar ε54Cr values). This age represents the earliest recorded evidence for planetary melting and volcanism in the Solar system, suggesting that the planetary crust formation occurred very early, only within the first few hundred thousand years of Solar system history. However, the 53Mn–53Cr age does not overlap with 26Al–26Mg dating results, which might indicate that non-carbonaceous achondrites have lower initial 26Al/27Al than the canonical value defined by refractory inclusions in carbonaceous chondrites.

Supplementary Table 1

Supplementary Figures 1-4

Presence of tumor-infiltrating lymphocytes (TIL) predicts survival in many cancer types. In HPV-driven cancers, cervical and oropharyngeal squamous cell carcinomas (CSCC and OPSCC, respectively), numbers of infiltrating T cells, particularly CD8+ T cells, and presentation of HPV E6/E7 epitopes are associated with improved prognosis. Endoplasmic reticulum aminopeptidase 1 (ERAP1) regulates the presented peptide repertoire, trimming peptide precursors prior to MHC I loading. ERAP1 is polymorphic, and allotypic variation of ERAP1 enzyme activity has an impact on the presented peptide repertoire. Individual SNPs are associated with incidence and outcome in a number of diseases, including CSCC. Here, we highlight the requirement for ERAP1 in the generation of HPV E6/E7 epitopes and show that the functional activity of ERAP1 allotype combinations identified in OPSCC correlate with tumor-infiltrating CD8+ T-cell (CD8)/TIL (CD8/TIL) status of the tumor. Functional analyses revealed that ERAP1 allotype combinations associated with CD8/TILlow tumors have a reduced capacity to generate both a model antigen SIINFEHL and the HPV-16 E782-90 epitope LLMGTLGIV from N-terminally extended precursor peptides. In contrast, ERAP1 allotypes from CD8/TILhigh tumors generated the epitopes efficiently. These data reveal that ERAP1 function correlates with CD8/TIL numbers and, by implication, prognosis, suggesting that the presentation of HPV-16 epitopes at the cell surface, resulting in an anti-HPV T-cell response, may depend on the ERAP1 allotype combinations expressed within an individual.

Supplementary Figure legends

The most effective responses to intracellular pathogens have a breadth of T-cell clones with different affinities for their cognate peptide, and a diversity of functional phenotypes, from effector to long-lived memory cells. While high- and low-affinity T-cells are inherently skewed towards becoming effector and memory, respectively, overall, both functional subsets exploit a wide range of affinities. How the breadth of affinities and functionalities are coordinated is therefore unclear. In this study, we provide evidence that direct sensing of the cytokine IFN-γ by CD8+T-cells is a factor controlling the integration of T-cell affinity and differentiation during infection. IFN-γ increases the expansion of low-affinity T-cells, allowing them to overcome the selective advantage of high-affinity T-cells. Concomitantly, IFN-γ reinforces high-affinity T-cell entry into the memory pool. As a result, direct IFN-γ sensing by CD8+T-cells increases the avidity of the memory response. This comes at the expense of the primary T-cell response, for which IFN-γ decreases the avidity, leading to sub-optimum immunity to infection. IFN-γ sensing by CD8+T-cells is paracrine, provided by a distinct subset of CD8+T-cells called Virtual Memory T-cells, an antigen inexperienced subset that harbors memory features. Overall, we propose that IFN-γ and Virtual Memory T-cells fulfil a critical immunoregulatory role by enabling the coordination of T-cell avidity and fate.

Drug development typically comprises a combination of pre-clinical experimentation, clinical trials, and statistical data-driven analyses. Therapeutic failure in late-stage clinical development costs the pharmaceutical industry billions of USD per year. Clinical trial simulation represents a key derisking strategy and combining them with mechanistic models allows one to test hypotheses for mechanisms of failure and to improve trial designs. This is illustrated with a T-cell activation model, used to simulate the clinical trials of IMA901, a short-peptide cancer vaccine. Simulation results were consistent with observed outcomes and predicted that responses are limited by peptide off-rates, peptide competition for dendritic cell (DC) binding, and DC migration times. These insights were used to hypothesise alternate trial designs predicted to improve efficacy outcomes. This framework illustrates how mechanistic models can complement clinical, experimental, and data-driven studies to understand, test, and improve trial designs, and how results may differ between humans and mice.

We document the utility for in situ Rb–Sr dating of a one-of-a-kind tribrid mass spectrometer, ‘Proteus’, coupled to a UV laser ablation system. Proteus combines quadrupole mass-filter, collision cell and sector magnet with a multicollection inductively-coupled plasma mass spectrometer (CC-MC-ICPMS/MS). Compared to commercial, single collector, tribrid inductively-coupled plasma mass spectrometers (CC-ICPMS/MS) Proteus has enhanced ion transmission and offers simultaneous collection of all Sr isotopes using an array of Faraday cups. These features yield improved precision in measured 87Sr/86Sr ratios, for a given mass of Sr analysed, approximately a factor of 25 in comparison to the Thermo Scientific™ iCAP TQ™ operated under similar conditions. Using SF6 as a reaction gas on Proteus, measurements of Rb-doped NIST SRM (standard reference material) 987 solutions, with Rb/Sr ratios from 0.01–100, yield 87Sr/86Sr that are indistinguishable from un-doped NIST SRM 987, demonstrating quantitative ‘chemical resolution’ of Rb from Sr. We highlight the importance of mass-filtering before the collision cell for laser ablation 87Sr/86Sr analysis, using an in-house feldspar standard and a range of glass reference materials. By transmitting only those ions with mass-to-charge ratios 82–92 u/e into the collision cell, we achieve accurate 87Sr/86Sr measurements without any corrections for atomic or polyatomic isobaric interferences. Without the pre-cell mass-filtering, measured in situ87Sr/86Sr ratios are inaccurate. Combining in situ measurements of Rb/Sr and radiogenic Sr isotope ratios we obtain mineral isochrons. We utilise a sample from the well-dated Dartmoor granite (285 ± 1 Ma) as a calibrant for our in situ ages and, using the same conditions, produce accurate Rb–Sr isochron ages for samples of the Fish Canyon tuff (28 ± 2 Ma) and Shap granite pluton (397 ± 1 Ma). Analysing the same Dartmoor granite sample using identical laser conditions and number of spot analyses using the Thermo Scientific™ iCAP TQ™ yielded an isochron slope 5× less precise than Proteus. We use an uncertainty model to illustrate the advantage of using Proteus over single collector CC-ICPMS/MS for in situ Rb–Sr dating. The results of this model show that the improvement is most marked for samples that have low Rb/Sr (, This paper highlights the capabilities of a novel tribrid mass spectrometer for rapid, in situ geological age determinations of typical crustal rocks and single, K-feldspars.

Esophageal adenocarcinoma (EAC) has a relatively poor long-term survival and limited treatment options. Promising targets for immunotherapy are short peptide neoantigens containing tumor mutations, presented to cytotoxic T-cells by human leukocyte antigen molecules (HLA). Despite an association between putative neoantigen abundance and therapeutic response across cancers, immunogenic neoantigens are challenging to identify. Here we characterized the mutational and immunopeptidomic landscapes of tumors from a cohort of seven patients with EAC. We directly identified one HLA-I presented neoantigen from one patient, and report functional T-cell responses from a predicted HLA-II neoantigen in a second patient. The predicted class II neoantigen contains both HLA I and II binding motifs. Our exploratory observations are consistent with previous neoantigen studies in finding that neoantigens are rarely directly observed, and an identification success rate following prediction in the order of 10%. However, our identified putative neoantigen is capable of eliciting strong T-cell responses, emphasizing the need for improved strategies for neoantigen identification.

Skin sensitization following the covalent modification of proteins by low molecular weight chemicals (haptenation) is mediated by cytotoxic T lymphocyte (CTL) recognition of human leukocyte antigen (HLA) molecules presented on the surface of almost all nucleated cells. There exist 3 nonmutually exclusive hypotheses for how haptens mediate CTL recognition: direct stimulation by haptenated peptides, hapten modification of HLA leading to an altered HLA-peptide repertoire, or a hapten altered proteome leading to an altered HLA-peptide repertoire. To shed light on the mechanism underpinning skin sensitization, we set out to utilize proteomic analysis of keratinocyte presented antigens following exposure to 2,4-dinitrochlorobenzene (DNCB). We show that the following DNCB exposure, cultured keratinocytes present cysteine haptenated (dinitrophenylated) peptides in multiple HLA molecules. In addition, we find that one of the DNCB modified peptides derives from the active site of cytosolic glutathione-S transferase-ω. These results support the current view that a key mechanism of skin sensitization is stimulation of CTLs by haptenated peptides. Data are available via ProteomeXchange with identifier PXD021373.

Dehydration of the subducting slab is a crucial process in the generation of hydrous convergent margin magmas, yet the exact processes of how and where the slab dehydrates and how these fluids are transported to the mantle wedge remain obscure. Strontium is a “fluid-mobile” element and as such well suited to investigate the source of slab-derived fluids. We employ mass-dependent Sr isotope systematics (δ88/86Sr; the deviation in 88Sr/86Sr of a sample relative to NIST SRM 987) of primitive arc lavas, in tandem with conventional radiogenic 87Sr/86Sr measurements, as a novel tracer of slab dehydration. To characterise the δ88/86Sr composition of subduction zone inputs, we present new δ88/86Sr data for subducting sediments, altered oceanic crust and MORB. Calcareous sediments are isotopically lighter and carbonate-free sediments are isotopically heavier than mid-ocean ridge basalts (MORB). Samples of the altered oceanic crust display elevated 87Sr/86Sr but only the most intensely altered sample has significantly higher δ88/86Sr than pristine MORB. Mafic arc lavas from the Aegean and Mariana arc invariably have a mass-dependent Sr isotope composition that is indistinguishable from MORB and lower 87Sr/86Sr than upper altered oceanic crust. This δ88/86Sr-87Sr/86Sr signature of the arc lavas, in combination with their high but variable Sr/Nd, can only be explained if it is provided by a fluid that acquired its Sr isotope signature in the deeper, less altered part of the subducted oceanic crust. We propose a model where the breakdown of serpentinite in the slab mantle releases a pulse of fluid at sub-arc depths. These fluids travel through and equilibrate with the overlying oceanic crust and induce wet partial melting of the upper altered crust and sediments. This hydrous melt is then delivered to the mantle source of arc magmas as a single metasomatic component. From mass balance it follows that the slab-derived fluid contributes >70% of the Sr budget of both Mariana and Aegean arc lavas. Whereas this fluid-dominated character is unsurprising for the sediment-poor Mariana arc, the Aegean arc sees the subduction of 3–6 km of calcareous sediments that were found to exert very little control on the Sr budget of the arc magmas and are overwhelmed by the fluid contribution.

Mid-ocean ridge basalts (MORB) reveal large mantle compositional heterogeneity, whose origin remains debated. Here we present a systematic study of molybdenum isotopes on well-characterized MORB glass samples from the East Pacific Rise (EPR) and near-EPR seamounts. Our analyses show significant Mo isotope variations with δ 98 / 95 Mo (relative to NIST SRM3134) ranging from −0.23‰ to −0.06‰. We argue that these Mo isotope variations are not caused by processes of MORB melt generation and evolution but reflect mantle isotopic heterogeneity. Taking together with the literature data, we show that MORB Mo isotope compositions vary systematically with geochemical parameters indicating mantle enrichment. These observations are best explained by two-component mixing between an incompatible element depleted endmember (e.g., low La/Sm, Nb/La, Nb/Zr and Th/Yb, and high Sm/Nd and 143Nd/144Nd) with low δ 98 / 95 Mo (∼−0.21‰) and an incompatible element enriched endmember (e.g., high La/Sm, Nb/La, Nb/Zr and Th/Yb, and low Sm/Nd and 143Nd/144Nd) with high δ 98 / 95 Mo (∼−0.05‰). The association of heavier Mo isotope compositions with the geochemically more enriched MORB is inconsistent with recycled ocean crust with or without sediment being the enriched endmember. Instead, this is consistent with the enriched endmember being of magmatic origin, most likely lithologies of low-degree melt metasomatic origin dispersed in the more depleted peridotite matrix in the MORB mantle. Thus, with MORB Mo isotope systematics, we confirm that recycled oceanic mantle lithosphere metasomatized by low degree melt plays a key role in the formation of E-MORB source lithologies. Our study also highlights Mo isotopes as an effective tool for studying upper mantle processes.

Governments are increasingly supporting initiatives to address plastic pollution, but efforts are largely opportunistic or driven by national socio-political priorities. There is an urgent need to move away from piecemeal single product instruments (e.g. single use plastic bag taxes or plastic straw bans) to deliver system-wide strategies that minimise the most pervasive sources of plastic pollution. Developing a common understanding of a jurisdiction’s plastic waste stream and the solutions available to decision-makers is vital to build consensus across stakeholders and to align on an evidence-based portfolio of priority instruments. This paper presents the Plastic Drawdown framework as a boundary-spanning tool to quickly create a coherent, relevant, and credible analysis and visualisation for stakeholders of plastic waste, leakage hotspots and minimisation opportunities. Using a new plastic waste modelling framework with a consultative structure, Plastic Drawdown explores plastic waste and leakage over a ten-year period and assesses impacts of policy instruments on this projection. Plastic Drawdown is adaptable to the data poor environment typical of many countries and designed as a rapid assessment tool to support the decision making of governments operating in a highly resource-constrained context. The Maldives is used as a case study to show the utility of the tool, where it highlighted strategies with the potential to reduce leakage of plastic waste into the marine environment by up to 85% by 2030. Plastic Drawdown built the case for phasing out single-use plastic waste across the Maldives and supported the Government’s decision to set ambitious targets, as announced at the United Nations General Assembly in 2019.

The last decade has seen widespread adoption of triple quadrupole-based inductively coupled plasma-tandem mass spectrometry (ICPMS/MS) technique using a collision/reaction cell in combination with a precell bandpass mass analyzer to measure isotopes otherwise masked by spectral interferences. High-precision isotope ratio analysis containing such isotopes would benefit from a similar capability on a multicollector inductively coupled plasma mass spectrometry (MC-ICPMS) platform, but using a quadrupole-based precell mass analyzer for MC-ICPMS/MS has several limitations. To overcome these limitations, we developed a novel precell mass analyzer for MC-ICPMS/MS using sector field technology. The new precell mass analyzer, comprising two Wien filters and a selection aperture, and a hexapole collision/reaction cell were integrated together in a single module and added to the commercially available Thermo Scientific Neptune XT MC-ICPMS to create a prototype MC-ICPMS/MS we named Vienna. Vienna was proven to retain the same performance of the base MC-ICPMS in terms of sensitivity, accuracy, and precision. Using the Vienna mass filter to eliminate Ar-based species, the abundance sensitivity achievable was equivalent to TIMS at mass 237.05, which was used to accurately determine the low 236U/238U isotope ratio of the uranium reference material IRMM184 (certified value, 1.2446 × 10-7). The performance of Vienna was then tested for a variety of geoscience applications that were expected to benefit from MC-ICPMS/MS technique, including Ca, K, Si, and in situ Rb/Sr dating by laser ablation.

We have determined Δ′26MgDSM-3, the mass-independent variations in 26Mg/24Mg, of primitive, bulk meteorites to precisions better than ±3 ppm (2se). Our measurements of samples from 10 different chondrite groups show Δ′26MgDSM-3 that vary from −5 to 22 ppm. Our data define an array with a positive slope in a plot of Δ′26MgDSM-3 against 27Al/24Mg, which can be used to determine (26Al/27Al)0, i.e. initial 26Al/27Al, and (Δ′26MgDSM-3)0, i.e. initial Δ′26MgDSM-3. On such an isochron plot, the best fit of our new measurements combined with literature data implies (26Al/27Al)0 of (4.67±0.78)×10−5 and (Δ′26MgDSM-3)0 of −31.6 ± 5.7 ppm (2se) for ordinary and carbonaceous chondrites, other than CR chondrites, which have anomalously low Δ′26MgDSM-3. These parameters are within uncertainty of those defined by previous measurements of bulk calcium-, aluminium-rich inclusions (CAIs) that set canonical (26Al/27Al)∼05×10−5. The most straightforward interpretation of all these observations is that differences in the Al/Mg of bulk ordinary and carbonaceous chondrites are dominantly controlled by variable contributions of early-formed refractory and major silicate components derived from a common, canonical reservoir. The Δ′26MgDSM-3 of enstatite chondrites are slightly more radiogenic (∼3 ppm) at similar Al/Mg to the ordinary chondrites. We speculate that this is related to the timing of removal of a refractory component from the source reservoirs of these different meteorite groups; the higher Δ′26MgDSM-3 of the enstatite chondrites suggests later (∼0.5 Ma post CAIs) condensation and loss of this refractory component. Despite inferred consistency of (26Al/27Al)0 and (Δ′26MgDSM-3)0 across most chondrite groups, some nebular heterogeneity is required to account for the compositions of CR chondrites. Our preferred interpretation is that the CR source region has lower (Δ′26MgDSM-3)0. As the most appropriate isotopic reference for the Earth, our new mean enstatite chondrite composition allows us to assess possible ingrowth of 26Mg from live 26Al during accretion of the Earth. The Earth has Δ′26MgDSM-3 within uncertainty of enstatite chondrites, despite its higher Al/Mg. This requires that the terrestrial increase in Al/Mg, which we attribute to vapour loss during accretion, must have happened >1.5 Ma post CAI formation, in an instantaneous fractionation model.

Presence of tumor-infiltrating lymphocytes (TIL) predicts survival in many cancer types. In HPV-driven cancers, cervical and oropharyngeal squamous cell carcinomas (CSCC and OPSCC, respectively), numbers of infiltrating T cells, particularly CD8+ T cells, and presentation of HPV E6/E7 epitopes are associated with improved prognosis. Endoplasmic reticulum aminopeptidase 1 (ERAP1) regulates the presented peptide repertoire, trimming peptide precursors prior to MHC I loading. ERAP1 is polymorphic, and allotypic variation of ERAP1 enzyme activity has an impact on the presented peptide repertoire. Individual SNPs are associated with incidence and outcome in a number of diseases, including CSCC. Here, we highlight the requirement for ERAP1 in the generation of HPV E6/E7 epitopes and show that the functional activity of ERAP1 allotype combinations identified in OPSCC correlate with tumor-infiltrating CD8+ T-cell (CD8)/TIL (CD8/TIL) status of the tumor. Functional analyses revealed that ERAP1 allotype combinations associated with CD8/TILlow tumors have a reduced capacity to generate both a model antigen SIINFEHL and the HPV-16 E782-90 epitope LLMGTLGIV from N-terminally extended precursor peptides. In contrast, ERAP1 allotypes from CD8/TILhigh tumors generated the epitopes efficiently. These data reveal that ERAP1 function correlates with CD8/TIL numbers and, by implication, prognosis, suggesting that the presentation of HPV-16 epitopes at the cell surface, resulting in an anti-HPV T-cell response, may depend on the ERAP1 allotype combinations expressed within an individual.

The promise of harnessing the immune system to fight cancer has long been dreamt of. In the late 19th century William Coley, a New York cancer surgeon, found that inflammation caused by purposely injecting streptococcal bacteria into sarcoma lesions could control the spread of the disease, at least temporarily. Over time, his ideas were left by the wayside as techniques in cancer surgery and radiotherapy were honed and the new science of chemotherapy was developed.

Recycling of the lithosphere via subduction drives the trace element and isotopic heterogeneity of the mantle, yet, the inventory of volatile elements in the diverse array of mantle reservoirs sampled at ocean islands remains uncertain. Boron is an ideal tracer of volatile recycling because it behaves similarly to volatiles during high-temperature geochemical reactions and carries a distinctive isotope signature into the mantle, but is subsequently little-influenced by degassing on return to the surface. Furthermore, B-rich recycled lithologies will have a strong influence on typical upper mantle compositions characterized by low B concentrations (11 B −7.1 ± 0.9‰). Here, we present and compare the B abundances and isotope compositions, together with the volatile element contents (H 2 O, CO 2 , and Cl) of basaltic glasses and olivine-hosted melt inclusions from two different ocean island localities (La Palma, Canary Islands, and Piton de Caille, La Réunion Island). Our results suggest that olivine hosted melt inclusions are protected from contamination during ascent and provide more robust estimates of primary mantle source δ 11 B than previous bulk rock studies. We find that the δ 11 B of the La Réunion samples (−7.9 ± 0.5‰ (2σ)) overlaps with the recently defined MORB datum, indicating that the depleted upper-mantle and ‘primitive mantle’ reservoirs are indistinguishable with respect to δ 11 B, or that B concentrations are sufficiently low that they are diluted by partial melting in the uppermost mantle. In contrast, the La Palma samples, notable for their radiogenic Pb isotope ratios, are characterized by δ 11 B values that are distinctly isotopically lighter (−10.5 ± 0.7‰ (2σ)) than La Réunion or MORB. We suggest these isotopically light values are derived from significantly dehydrated recycled materials preserved in the La Palma mantle source region, in keeping with their lower B/Zr and H 2 O/Ce. This work therefore provides strong new support for subduction zone processing as a mechanism for generating radiogenic Pb isotopic signatures and volatiles heterogeneities in the mantle.