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<jats:title>Abstract</jats:title><jats:p>Diatoms account for up to 40% of marine primary production<jats:sup>1,2</jats:sup> and require silicic acid to grow and build their opal shell<jats:sup>3</jats:sup>. On the physiological and ecological level, diatoms are thought to be resistant to, or even benefit from, ocean acidification<jats:sup>4–6</jats:sup>. Yet, global-scale responses and implications for biogeochemical cycles in the future ocean remain largely unknown. Here we conducted five in situ mesocosm experiments with natural plankton communities in different biomes and find that ocean acidification increases the elemental ratio of silicon (Si) to nitrogen (N) of sinking biogenic matter by 17 ± 6 per cent under <jats:inline-formula><jats:alternatives><jats:tex-math>$${{p}}_{{{\rm{CO}}}_{2}}$$</jats:tex-math><mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msub> <mml:mrow> <mml:mi>p</mml:mi> </mml:mrow> <mml:mrow> <mml:msub> <mml:mi>CO</mml:mi> <mml:mrow> <mml:mn>2</mml:mn> </mml:mrow> </mml:msub> </mml:mrow> </mml:msub> </mml:math></jats:alternatives></jats:inline-formula> conditions projected for the year 2100. This shift in Si:N seems to be caused by slower chemical dissolution of silica at decreasing seawater pH. We test this finding with global sediment trap data, which confirm a widespread influence of pH on Si:N in the oceanic water column. Earth system model simulations show that a future pH-driven decrease in silica dissolution of sinking material reduces the availability of silicic acid in the surface ocean, triggering a global decline of diatoms by 13–26 per cent due to ocean acidification by the year 2200. This outcome contrasts sharply with the conclusions of previous experimental studies, thereby illustrating how our current understanding of biological impacts of ocean change can be considerably altered at the global scale through unexpected feedback mechanisms in the Earth system.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Immunotherapies have achieved remarkable successes in the treatment of cancer, but major challenges remain<jats:sup>1,2</jats:sup>. An inherent weakness of current treatment approaches is that therapeutically targeted pathways are not restricted to tumours, but are also found in other tissue microenvironments, complicating treatment<jats:sup>3,4</jats:sup>. Despite great efforts to define inflammatory processes in the tumour microenvironment, the understanding of tumour-unique immune alterations is limited by a knowledge gap regarding the immune cell populations in inflamed human tissues. Here, in an effort to identify such tumour-enriched immune alterations, we used complementary single-cell analysis approaches to interrogate the immune infiltrate in human head and neck squamous cell carcinomas and site-matched non-malignant, inflamed tissues. Our analysis revealed a large overlap in the composition and phenotype of immune cells in tumour and inflamed tissues. Computational analysis identified tumour-enriched immune cell interactions, one of which yields a large population of regulatory T (T<jats:sub>reg</jats:sub>) cells that is highly enriched in the tumour and uniquely identified among all haematopoietically-derived cells in blood and tissue by co-expression of ICOS and IL-1 receptor type 1 (IL1R1). We provide evidence that these intratumoural IL1R1<jats:sup>+</jats:sup> T<jats:sub>reg</jats:sub> cells had responded to antigen recently and demonstrate that they are clonally expanded with superior suppressive function compared with IL1R1<jats:sup>−</jats:sup> T<jats:sub>reg</jats:sub> cells. In addition to identifying extensive immunological congruence between inflamed tissues and tumours as well as tumour-specific changes with direct disease relevance, our work also provides a blueprint for extricating disease-specific changes from general inflammation-associated patterns.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Phosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for treatment of B cell malignancies<jats:sup>1–3</jats:sup>. Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity<jats:sup>4,5</jats:sup>, its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (T<jats:sub>reg</jats:sub>) cells and enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses of AMG319, immune-related adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic effects on T<jats:sub>reg</jats:sub> cells. Accordingly, in mouse models, PI3Kδi decreased the number of T<jats:sub>reg</jats:sub> cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 T<jats:sub>reg</jats:sub> cells, accompanied by expansion of pathogenic T helper 17 (T<jats:sub>H</jats:sub>17) and type 17 CD8<jats:sup>+</jats:sup> T (T<jats:sub>C</jats:sub>17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity.</jats:p>