Decoupling the correlation between cytotoxic and exhausted T lymphocyte states enhances melanoma immunotherapy response prediction.

Cytotoxic T lymphocyte (CTL) and terminal exhausted T lymphocyte (ETL) activities crucially influence immune checkpoint inhibitor (ICI) response. Despite this, the efficacy of ETL and CTL transcriptomic signatures for response prediction remains limited. Investigating this across the TCGA and publicly available single-cell cohorts, we find a strong positive correlation between ETL and CTL expression signatures in most cancers. We hence posited that their limited predictability arises due to their mutually canceling effects on ICI response. Thus, we developed DETACH, a computational method to identify a gene set whose expression pinpoints to a subset of melanoma patients where the CTL and ETL correlation is low. DETACH enhances CTL's prediction accuracy, outperforming existing signatures. DETACH signature genes activity also demonstrates a positive correlation with lymphocyte infiltration and the prevalence of reactive T cells in the tumor microenvironment (TME), advancing our understanding of the CTL cell state within the TME.

Deactivation of ligand-receptor interactions enhancing lymphocyte infiltration drives melanoma resistance to Immune Checkpoint Blockade.

Immune checkpoint blockade (ICB) is a promising cancer therapy; however, resistance often develops. To learn more about ICB resistance mechanisms, we developed IRIS (Immunotherapy Resistance cell-cell Interaction Scanner), a machine learning model aimed at identifying candidate ligand-receptor interactions (LRI) that are likely to mediate ICB resistance in the tumor microenvironment (TME). We developed and applied IRIS to identify resistance-mediating cell-type-specific ligand-receptor interactions by analyzing deconvolved transcriptomics data of the five largest melanoma ICB therapy cohorts. This analysis identifies a set of specific ligand-receptor pairs that are deactivated as tumors develop resistance, which we refer to as resistance deactivated interactions (RDI). Quite strikingly, the activity of these RDIs in pre-treatment samples offers a markedly stronger predictive signal for ICB therapy response compared to those that are activated as tumors develop resistance. Their predictive accuracy surpasses the state-of-the-art published transcriptomics biomarker signatures across an array of melanoma ICB datasets. Many of these RDIs are involved in chemokine signaling. Indeed, we further validate on an independent large melanoma patient cohort that their activity is associated with CD8+ T cell infiltration and enriched in hot/brisk tumors. Taken together, this study presents a new strongly predictive ICB response biomarker signature, showing that following ICB treatment resistant tumors turn inhibit lymphocyte infiltration by deactivating specific key ligand-receptor interactions.

Remanufacturing and energy savings.

Remanufactured products that can substitute for new products are generally claimed to save energy. These claims are made from studies that look mainly at the differences in materials production and manufacturing. However, when the use phase is included, the situation can change radically. In this Article, 25 case studies for eight different product categories were studied, including: (1) furniture, (2) clothing, (3) computers, (4) electric motors, (5) tires, (6) appliances, (7) engines, and (8) toner cartridges. For most of these products, the use phase energy dominates that for materials production and manufacturing combined. As a result, small changes in use phase efficiency can overwhelm the claimed savings from materials production and manufacturing. These use phase energy changes are primarily due to efficiency improvements in new products, and efficiency degradation in remanufactured products. For those products with no, or an unchanging, use phase energy requirement, remanufacturing can save energy. For the 25 cases, we found that 8 cases clearly saved energy, 6 did not, and 11 were too close to call. In some cases, we could examine how the energy savings potential of remanufacturing has changed over time. Specifically, during times of significant improvements in energy efficiency, remanufacturing would often not save energy. A general design trend seems to be to add power to a previously unpowered product, and then to improve on the energy efficiency of the product over time. These trends tend to undermine the energy savings potential of remanufacturing.

Why we use more materials.

In this paper, we review the drivers for the high levels of material use in society, investigating both historical and current trends. We present recent national and global data by different material categories and accounting schemes, showing the correlations between materials use and different measures of human well-being. We also present a development narrative to accompany these observed trends, focusing on the strong role materials have played in economic development by industrialization and in the consumer economy. Finally, we speculate on how material efficiency might alter this pattern going forward and whether it is possible to de-couple well-being from material use.This article is part of the themed issue 'Material demand reduction'.

The energy required to produce materials: constraints on energy-intensity improvements, parameters of demand.

In this paper, we review the energy requirements to make materials on a global scale by focusing on the five construction materials that dominate energy used in material production: steel, cement, paper, plastics and aluminium. We then estimate the possibility of reducing absolute material production energy by half, while doubling production from the present to 2050. The goal therefore is a 75 per cent reduction in energy intensity. Four technology-based strategies are investigated, regardless of cost: (i) widespread application of best available technology (BAT), (ii) BAT to cutting-edge technologies, (iii) aggressive recycling and finally, and (iv) significant improvements in recycling technologies. Taken together, these aggressive strategies could produce impressive gains, of the order of a 50-56 per cent reduction in energy intensity, but this is still short of our goal of a 75 per cent reduction. Ultimately, we face fundamental thermodynamic as well as practical constraints on our ability to improve the energy intensity of material production. A strategy to reduce demand by providing material services with less material (called 'material efficiency') is outlined as an approach to solving this dilemma.