Catálogo de publicaciones - revistas

<jats:title>Abstract</jats:title><jats:p>Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance<jats:sup>1,2</jats:sup>. The protein tyrosine phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour cells or immune cells promotes anti-tumour immunity<jats:sup>3–6</jats:sup>. However, phosphatases are challenging drug targets; in particular, the active site has been considered undruggable. Here we present the discovery and characterization of ABBV-CLS-484 (AC484), a first-in-class, orally bioavailable, potent PTPN2 and PTPN1 active-site inhibitor. AC484 treatment in vitro amplifies the response to interferon and promotes the activation and function of several immune cell subsets. In mouse models of cancer resistant to PD-1 blockade, AC484 monotherapy generates potent anti-tumour immunity. We show that AC484 inflames the tumour microenvironment and promotes natural killer cell and CD8<jats:sup>+</jats:sup> T cell function by enhancing JAK–STAT signalling and reducing T cell dysfunction. Inhibitors of PTPN2 and PTPN1 offer a promising new strategy for cancer immunotherapy and are currently being evaluated in patients with advanced solid tumours (ClinicalTrials.gov identifier <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://www.clinicaltrials.gov/study/NCT04777994?term=NCT04777994&amp;rank=1">NCT04777994</jats:ext-link>). More broadly, our study shows that small-molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to or exceeding that of antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge, AC484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics that target this important class of enzymes.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Mountain uplift and erosion have regulated the balance of carbon between Earth’s interior and atmosphere, where prior focus has been placed on the role of silicate mineral weathering in CO<jats:sub>2</jats:sub> drawdown and its contribution to the stability of Earth’s climate in a habitable state<jats:sup>1–5</jats:sup>. However, weathering can also release CO<jats:sub>2</jats:sub> as rock organic carbon (OC<jats:sub>petro</jats:sub>) is oxidized at the near surface<jats:sup>6,7</jats:sup>; this important geological CO<jats:sub>2</jats:sub> flux has remained poorly constrained<jats:sup>3,8</jats:sup>. We use the trace element rhenium in combination with a spatial extrapolation model to quantify this flux across global river catchments<jats:sup>3,9</jats:sup>. We find a CO<jats:sub>2</jats:sub> release of <jats:inline-formula><jats:alternatives><jats:tex-math>$${68}_{-6}^{+18}$$</jats:tex-math><mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msubsup> <mml:mrow> <mml:mn>68</mml:mn> </mml:mrow> <mml:mrow> <mml:mo>−</mml:mo> <mml:mn>6</mml:mn> </mml:mrow> <mml:mrow> <mml:mo>+</mml:mo> <mml:mn>18</mml:mn> </mml:mrow> </mml:msubsup> </mml:math></jats:alternatives></jats:inline-formula> megatons of carbon annually from weathering of OC<jats:sub>petro</jats:sub> in near-surface rocks, rivalling or even exceeding the CO<jats:sub>2</jats:sub> drawdown by silicate weathering at the global scale<jats:sup>10</jats:sup>. Hotspots of CO<jats:sub>2</jats:sub> release are found in mountain ranges with high uplift rates exposing fine-grained sedimentary rock, such as the eastern Himalayas, the Rocky Mountains and the Andes. Our results demonstrate that OC<jats:sub>petro</jats:sub> is far from inert and causes weathering in regions to be net sources or sinks of CO<jats:sub>2</jats:sub>. This raises questions, not yet fully studied, as to how erosion and weathering drive the long-term carbon cycle and contribute to the fine balance of carbon fluxes between the atmosphere, biosphere and lithosphere<jats:sup>2,11</jats:sup>.</jats:p>