NKG2D is a danger sensor expressed on different subsets of innate and adaptive lymphocytes. This study demonstrates how NKG2D enforces proinflammatory features of Th1 and Th17 cells and promotes inflammation in vivo, identifying NKG2D as an important target for the amelioration of Th1/ Th17-mediated inflammatory diseases.
Type 1 conventional dendritic cells are systemically dysregulated early in pancreatic carcinogenesis
Type 1 conventional dendritic cells are progressively and systemically dysregulated during pancreatic carcinogenesis, subject to semimaturation and IL-6–driven apoptosis. Yet, CD40 agonist synergizes with Flt3L to rescue cDC1 abundance and maturation, enabling a return to full CD8+ T cell priming.
Distinct fibroblast functional states drive clinical outcomes in ovarian cancer and are regulated by TCF21
In this study, Hussain et al. demonstrate that cancer-associated fibroblasts (CAFs) in high-grade serous ovarian cancer are heterogeneous, that CAF state drives cancer aggressiveness and patient outcomes, and that TCF21 is a master regulator of CAF state.
Wu et al. show that nicotine promotes brain metastasis of lung cancer by skewing polarity of M2 microglia and suppressing their phagocytic ability and show that this process is blocked by the natural compound parthenolide.
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T reg–specific insulin receptor deletion prevents diet-induced and age-associated metabolic syndrome
Insulin receptor deletion in T regs improves metabolic outcomes in models of diet- and age-induced obesity and hyperinsulinemia. Direct effects of hyperinsulinemia on T regs is a previously unknown mechanism controlling T reg function in metabolic syndrome.
This study demonstrates that, in a mouse model of ALS, excitatory synapses on spinal motoneurons are disrupted. Activation of the cAMP/PKA pathway reverts the functional and structural synaptic deficits and ameliorates disease markers by increasing motoneuron firing.
Targeting CLK3 inhibits the progression of cholangiocarcinoma by reprogramming nucleotide metabolism
Zhou et al. characterize a critical role of CLK3 on purine metabolism in cholangiocarcinoma (CCA). Overexpressed or mutated CLK3 promotes CCA progression in vitro and in vivo. Therefore, CLK3 may serve as a biomarker and potential drug target for CCA.
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Here Bhattacharyya et al. show that MYC is a molecular point of convergence for microenvironmental and cell-autonomous signals in RAS-transformed pancreatic cancer cells. They identify cancer-associated fibroblast–derived FGF1 as a critical paracrine regulator of MYC, and a novel link between the pancreatic tumor microenvironment and oncogenic transcription.
Lim et al. show that the integrin adaptor talin1 controls dendritic cell activation and maturation by promoting the formation of preassembled TLR complexes in steady state and signalosome assembly upon ligand binding via novel direct interactions with MyD88 and PIP5K. Talin1 controls TLR-signaling pathways through scaffolding Myddosome in DCs and thereby influences inflammatory responses in vivo.
Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells
Metabolic constrains induce transcriptional deregulation of CD8+ T cells in pancreatic tumor microenvironment, driving progressive dysfunction. Here, metabolic reprogramming through enforced very-long-chain acyl-CoA dehydrogenase expression enhances intratumor T cells survival and persistence, overcoming a major hurdle to immunotherapy for PDA.
Meng et al. identify YAP as a mechanosensor in T cells that suppresses metabolism and effector activity in mechanically soft tissues and accentuates in stiff ones.