RESUMEN
BACKGROUND: Immune checkpoint therapy (ICT) provides durable responses in select cancer patients, yet resistance remains a significant challenge, prompting the exploration of underlying molecular mechanisms. Tyrosylprotein sulfotransferase-2 (TPST2), known for its role in protein tyrosine O-sulfation, has been suggested to modulate the extracellular protein-protein interactions, but its specific role in cancer immunity remains largely unexplored. METHODS: To explore tumor cell-intrinsic factors influencing anti-PD1 responsiveness, we conducted a pooled loss-of-function genetic screen in humanized mice engrafted with human immune cells. The responsiveness of cancer cells to interferon-γ (IFNγ) was estimated by evaluating IFNγ-mediated induction of target genes, STAT1 phosphorylation, HLA expression, and cell growth suppression. The sulfotyrosine-modified target gene of TPST2 was identified by co-immunoprecipitation and mass spectrometry. The in vivo effects of TPST2 inhibition were evaluated using mouse syngeneic tumor models and corroborated by bulk and single-cell RNA sequencing analyses. RESULTS: Through in vivo genome-wide CRISPR screening, TPST2 loss-of-function emerged as a potential enhancer of anti-PD1 treatment efficacy. TPST2 suppressed IFNγ signaling by sulfating IFNγ receptor 1 at Y397 residue, while its downregulation boosted IFNγ-mediated signaling and antigen presentation. Depletion of TPST2 in cancer cells augmented anti-PD1 antibody efficacy in syngeneic mouse tumor models by enhancing tumor-infiltrating lymphocytes. RNA sequencing data revealed TPST2's inverse correlation with antigen presentation, and increased TPST2 expression is associated with poor prognosis and altered cancer immunity across cancer types. CONCLUSIONS: We propose TPST2's novel role as a suppressor of cancer immunity and advocate for its consideration as a therapeutic target in ICT-based treatments.
Asunto(s)
Receptor de Muerte Celular Programada 1 , Sulfotransferasas , Animales , Humanos , Ratones , Sulfotransferasas/genética , Sulfotransferasas/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Línea Celular Tumoral , Interferón gamma/metabolismo , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Sistemas CRISPR-Cas , Ensayos Antitumor por Modelo de Xenoinjerto , Neoplasias/genética , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/metabolismo , Modelos Animales de EnfermedadRESUMEN
One pot synthesis of RhCu alloy truncated octahedral nanoframes, Cu@Rh core-shell nanoparticles, and a bundle of five RhCu nanowires is demonstrated. The RhCu alloy 3D nanoframe, in particular, exhibits excellent catalytic activity toward the oxygen evolution reaction under alkaline conditions.
RESUMEN
Multimetallic nanocatalysts with a controlled structure can provide enhanced catalytic activity and durability by exploiting electronic, geometric, and strain effects. Herein, we report the synthesis of a novel ternary nanocatalyst based on Mo doped PtNi dendritic nanowires (Mo-PtNi DNW) and its bifunctional application in the methanol oxidation reaction (MOR) at the anode and the oxygen reduction reaction (ORR) at the cathode for direct methanol fuel cells. An unprecedented Mo-PtNi DNW structure can combine multiple structural attributes of the 1D nanowire morphology and dendritic surfaces. In the MOR, Mo-PtNi DNW exhibits superior activity to Pt/C and Mo doped Pt dendritic nanowires (Mo-Pt DNW), and excellent durability. Furthermore, Mo-PtNi DNW demonstrates excellent activity and durability for the ORR. This work highlights the important role of compositional and structural control in nanocatalysts for boosting catalytic performances.
RESUMEN
OBJECTIVE: To identify the range of the terminal motor points of the triceps surae muscles in relation to bony landmarks. DESIGN: Eight limbs of four male cadavers were anatomically dissected. The range of terminal motor points from the tibial nerve to each triceps surae muscle was identified related to the bony landmarks. Bony landmarks were medial and lateral epicondyles of the femur and medial and lateral malleoli of the tibia. The length of the lower leg was defined as the distance from the intercondylar line of the femur to the intermalleolar line of the tibia. The locations of the motor points were expressed as the percentage of the length of the lower leg. RESULTS: The motor points of the medial gastrocnemius, lateral gastrocnemius, and soleus muscles were diffusely distributed along the muscle longitudinal bulk. The highest motor points of the medial gastrocnemius, lateral gastrocnemius, and soleus were located in 9.6% +/- 3.5%, 12.0% +/- 3.4%, and 20.5% +/- 3.9%, respectively, of the length of the lower leg. The lowest motor points were located in 37.5% +/- 5.5%, 37.9% +/- 2.3%, and 46.7% +/- 3.6%, respectively, of the length of the lower leg. CONCLUSIONS: The present study defined the longitudinal distribution pattern of terminal motor points in the triceps surae muscles. This concept can be helpful for further studies evaluating the effectiveness of the botulinum toxin injection method.