FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4290375462> ?p ?o ?g. }

• W4290375462 endingPage "1612" @default.
• W4290375462 startingPage "1593" @default.
• W4290375462 abstract "We have shown that reciprocally activated rat sarcoma (RAS)/mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) and Janus kinase/signal transducer and activator of transcription 3 (STAT3) pathways mediate therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC), while combined MEK and STAT3 inhibition (MEKi+STAT3i) overcomes such resistance and alters stromal architecture. We now determine whether MEKi+STAT3i reprograms the cancer-associated fibroblast (CAF) and immune microenvironment to overcome resistance to immune checkpoint inhibition in PDAC.CAF and immune cell transcriptomes in MEKi (trametinib)+STAT3i (ruxolitinib)-treated vs vehicle-treated Ptf1aCre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) tumors were examined via single-cell RNA sequencing (scRNAseq). Clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeats associated protein 9 silencing of CAF-restricted Map2k1/Mek1 or Stat3, or both, enabled interrogation of CAF-dependent effects on immunologic remodeling in orthotopic models. Tumor growth, survival, and immune profiling via mass cytometry by time-of-flight were examined in PKT mice treated with vehicle, anti-programmed cell death protein 1 (PD-1) monotherapy, and MEKi+STAT3i combined with anti-PD1.MEKi+STAT3i attenuates Il6/Cxcl1-expressing proinflammatory and Lrrc15-expressing myofibroblastic CAF phenotypes while enriching for Ly6a/Cd34-expressing CAFs exhibiting mesenchymal stem cell-like features via scRNAseq in PKT mice. This CAF plasticity is associated with M2-to-M1 reprogramming of tumor-associated macrophages, and enhanced trafficking of cluster of differentiation 8+ T cells, which exhibit distinct effector transcriptional programs. These MEKi+STAT3i-induced effects appear CAF-dependent, because CAF-restricted Mek1/Stat3 silencing mitigates inflammatory-CAF polarization and myeloid infiltration in vivo. Addition of MEKi+STAT3i to PD-1 blockade not only dramatically improves antitumor responses and survival in PKT mice but also augments recruitment of activated/memory T cells while improving their degranulating and cytotoxic capacity compared with anti-PD-1 monotherapy. Importantly, treatment of a patient who has chemotherapy-refractory metastatic PDAC with MEKi (trametinib), STAT3i (ruxolitinib), and PD-1 inhibitor (nivolumab) yielded clinical benefit.Combined MEKi+STAT3i mitigates stromal inflammation and enriches for CAF phenotypes with mesenchymal stem cell-like properties to overcome immunotherapy resistance in PDAC." @default.
• W4290375462 created "2022-08-07" @default.
• W4290375462 creator A5001060160 @default.
• W4290375462 creator A5012159224 @default.
• W4290375462 creator A5016606073 @default.
• W4290375462 creator A5034445995 @default.
• W4290375462 creator A5059146573 @default.
• W4290375462 creator A5064761055 @default.
• W4290375462 creator A5065012486 @default.
• W4290375462 creator A5067118030 @default.
• W4290375462 creator A5068034590 @default.
• W4290375462 creator A5072337663 @default.
• W4290375462 creator A5075604861 @default.
• W4290375462 creator A5077311762 @default.
• W4290375462 creator A5081500761 @default.
• W4290375462 creator A5081706310 @default.
• W4290375462 creator A5085573879 @default.
• W4290375462 creator A5089529776 @default.
• W4290375462 date "2022-12-01" @default.
• W4290375462 modified "2023-10-06" @default.
• W4290375462 title "Combined MEK and STAT3 Inhibition Uncovers Stromal Plasticity by Enriching for Cancer-Associated Fibroblasts With Mesenchymal Stem Cell-Like Features to Overcome Immunotherapy Resistance in Pancreatic Cancer" @default.
• W4290375462 cites W1547462939 @default.
• W4290375462 cites W1820142295 @default.
• W4290375462 cites W1996912024 @default.
• W4290375462 cites W2018159884 @default.
• W4290375462 cites W2019517037 @default.
• W4290375462 cites W2137357003 @default.
• W4290375462 cites W2140946995 @default.
• W4290375462 cites W2153091619 @default.
• W4290375462 cites W2168478794 @default.
• W4290375462 cites W2175707253 @default.
• W4290375462 cites W2236482561 @default.
• W4290375462 cites W2284388501 @default.
• W4290375462 cites W2416038770 @default.
• W4290375462 cites W2514792180 @default.
• W4290375462 cites W2541831810 @default.
• W4290375462 cites W2582033455 @default.
• W4290375462 cites W2590390825 @default.
• W4290375462 cites W2609921003 @default.
• W4290375462 cites W2618915943 @default.
• W4290375462 cites W2732928415 @default.
• W4290375462 cites W2761575992 @default.
• W4290375462 cites W2794986280 @default.
• W4290375462 cites W2888987731 @default.
• W4290375462 cites W2896772159 @default.
• W4290375462 cites W2898435366 @default.
• W4290375462 cites W2936366750 @default.
• W4290375462 cites W2947548345 @default.
• W4290375462 cites W2951222857 @default.
• W4290375462 cites W2959096163 @default.
• W4290375462 cites W2964097765 @default.
• W4290375462 cites W2969959193 @default.
• W4290375462 cites W2980314475 @default.
• W4290375462 cites W2984359187 @default.
• W4290375462 cites W2986162201 @default.
• W4290375462 cites W2988788707 @default.
• W4290375462 cites W2997277554 @default.
• W4290375462 cites W3003058300 @default.
• W4290375462 cites W3020400196 @default.
• W4290375462 cites W3023906975 @default.
• W4290375462 cites W3026844837 @default.
• W4290375462 cites W3027719703 @default.
• W4290375462 cites W3044807317 @default.
• W4290375462 cites W3123827788 @default.
• W4290375462 cites W3199237048 @default.
• W4290375462 cites W4225596827 @default.
• W4290375462 cites W4229052987 @default.
• W4290375462 doi "https://doi.org/10.1053/j.gastro.2022.07.076" @default.
• W4290375462 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/35948109" @default.
• W4290375462 hasPublicationYear "2022" @default.
• W4290375462 type Work @default.
• W4290375462 citedByCount "30" @default.
• W4290375462 countsByYear W42903754622022 @default.
• W4290375462 countsByYear W42903754622023 @default.
• W4290375462 crossrefType "journal-article" @default.
• W4290375462 hasAuthorship W4290375462A5001060160 @default.
• W4290375462 hasAuthorship W4290375462A5012159224 @default.
• W4290375462 hasAuthorship W4290375462A5016606073 @default.
• W4290375462 hasAuthorship W4290375462A5034445995 @default.
• W4290375462 hasAuthorship W4290375462A5059146573 @default.
• W4290375462 hasAuthorship W4290375462A5064761055 @default.
• W4290375462 hasAuthorship W4290375462A5065012486 @default.
• W4290375462 hasAuthorship W4290375462A5067118030 @default.
• W4290375462 hasAuthorship W4290375462A5068034590 @default.
• W4290375462 hasAuthorship W4290375462A5072337663 @default.
• W4290375462 hasAuthorship W4290375462A5075604861 @default.
• W4290375462 hasAuthorship W4290375462A5077311762 @default.
• W4290375462 hasAuthorship W4290375462A5081500761 @default.
• W4290375462 hasAuthorship W4290375462A5081706310 @default.
• W4290375462 hasAuthorship W4290375462A5085573879 @default.
• W4290375462 hasAuthorship W4290375462A5089529776 @default.
• W4290375462 hasBestOaLocation W42903754621 @default.
• W4290375462 hasConcept C16930146 @default.
• W4290375462 hasConcept C171958077 @default.
• W4290375462 hasConcept C198826908 @default.
• W4290375462 hasConcept C203014093 @default.
• W4290375462 hasConcept C2776107976 @default.
• W4290375462 hasConcept C2777701055 @default.

• next