FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4308407188> ?p ?o ?g. }

• W4308407188 abstract "<h3>Background</h3> PD-(L)1 immune checkpoint blockade (ICB) therapy yields objective responses in 15-25% of patients with bladder cancer (BC), suggesting that tumor-associated resistance mechanisms undermine their efficacy.^1-6 We previously identified two gene signatures derived from pre-treatment tumor tissue independently associated with ICB outcomes in BC patients: 1) a signature enriched in adaptive immune response genes and associated with better ICB outcomes named the “adaptive immune response signature” and 2) a signature enriched in innate immune and inflammation genes and associated with worse ICB outcomes labelled the “pro-tumorigenic inflammation signature”.⁷ The adaptive immune response: pro-tumorigenic inflammation score ratio, named the 2IR score, was highly correlated with ICB response and validated in an independent cohort. <h3>Methods</h3> Single-cell RNA sequencing (scRNAseq) was performed on BC tumors (n=26) and normal-adjacent tissue (n=3) to resolve the cellular composition underlying the 2IR score. Ingenuity Pathway Analysis was applied to predict upstream ligands skewing MΦ phenotypes and such ligands were tested for their effects on healthy donor peripheral blood monocytes differentiated with (G)M-CSF. Patient plasma was assessed for pro-inflammatory cytokines across disease stage using O-Link Proteomics and Enzyme-Linked ImmunoSorbent Assay. <h3>Results</h3> From our scRNAseq, we discovered the adaptive immune response and pro-tumorigenic inflammation signatures were enriched in distinct MΦ subsets we labelled immunostimulatory (is)MΦs and pro-tumorigenic (pt)MΦs, respectively. ptMΦs upregulated inflammatory markers: SPP1, TREM1, and CLEC5A; expressed pro-angiogenic and hypoxic programs; and downregulated antigen presentation machinery. ptMΦs were enriched in tumor versus normal-adjacent tissue, which was confirmed by flow cytometry on additional patients. From our screen of predicted upstream ligands, lipopolysaccharide (LPS) induced the highest amount of ptMΦs (p<.05), as defined by Clec5a and Trem1 surface expression, in GM-CSF-induced MΦs, while IL-1β induced the most for M-CSF-induced MΦs (p<.005). ptMΦs also upregulated SPP1 on a transcriptional level. Inflammatory cytokines (e.g. IL-1β, IL-6, IL-8) as well as macrophage-colony stimulating factor (CSF-1) were elevated in the plasma of advanced stage BC patients as compared to early stage and healthy donors. <h3>Conclusions</h3> From our BC scRNAseq cohort, we discovered a pro-tumorigenic inflammatory MΦ subset underlying a gene signature previously linked to ICB resistance in bladder cancer. We recapitulated these MΦs using blood monocytes differentiated with G(M)-CSF and skewed with LPS/IL-1β. We also found inflammatory cytokines associated with these MΦs were elevated in the peripheral blood of advanced patients. Together, these findings identify a distinct MΦ transcriptional state that may underlie tumor-promoting inflammation and ICB resistance and be therapeutically modulated to overcome ICB resistance. <h3>References</h3> Sharma P, <i>et al</i>. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. <i>The Lancet Oncology</i> 2017;<b>18</b>, 312–322 . Rosenberg JE, <i>et al</i>. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: A single-arm, multicentre, phase 2 trial. <i>The Lancet</i> 2016;<b>387</b>:1909–1920. Bellmunt J, <i>et al</i>. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. <i>New England Journal of Medicine</i> 2017;<b>376</b>:1015–1026. Patel MR, <i>et al</i>. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. <i>The Lancet Oncology</i> 2018;<b>19</b>:51–64. Powles T, <i>et al</i>. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: Updated results from a phase 1/2 open-label study. <i>JAMA Oncology</i> 2017;<b>3</b>:1–10. Powles T, <i>et al</i>. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. <i>Nature</i> 2014;<b>515</b>:558–562. Wang L, <i>et al</i>. Myeloid Cell–associated Resistance to PD-1/PD-L1 Blockade in Urothelial Cancer Revealed Through Bulk and Single-cell RNA Sequencing. <i>Clinical Cancer Research</i> 2021;1–15, doi:10.1158/1078-0432.ccr-20-4574. <h3>Ethics Approval</h3> The study was approved by Mount Sinai Institution9s Ethics Board, approval number 10-1180. <h3>Consent</h3> Participants gave informed consent before taking part in the study." @default.
• W4308407188 created "2022-11-11" @default.
• W4308407188 creator A5010082766 @default.
• W4308407188 creator A5018275141 @default.
• W4308407188 creator A5026912903 @default.
• W4308407188 creator A5031802345 @default.
• W4308407188 creator A5055358847 @default.
• W4308407188 creator A5078522441 @default.
• W4308407188 creator A5083361833 @default.
• W4308407188 date "2022-11-01" @default.
• W4308407188 modified "2023-09-25" @default.
• W4308407188 title "946 Dissecting myeloid cell-mediated mechanisms of resistance to immune checkpoint blockade in bladder cancer" @default.
• W4308407188 doi "https://doi.org/10.1136/jitc-2022-sitc2022.0946" @default.
• W4308407188 hasPublicationYear "2022" @default.
• W4308407188 type Work @default.
• W4308407188 citedByCount "0" @default.
• W4308407188 crossrefType "proceedings-article" @default.
• W4308407188 hasAuthorship W4308407188A5010082766 @default.
• W4308407188 hasAuthorship W4308407188A5018275141 @default.
• W4308407188 hasAuthorship W4308407188A5026912903 @default.
• W4308407188 hasAuthorship W4308407188A5031802345 @default.
• W4308407188 hasAuthorship W4308407188A5055358847 @default.
• W4308407188 hasAuthorship W4308407188A5078522441 @default.
• W4308407188 hasAuthorship W4308407188A5083361833 @default.
• W4308407188 hasBestOaLocation W43084071881 @default.
• W4308407188 hasConcept C104317684 @default.
• W4308407188 hasConcept C121608353 @default.
• W4308407188 hasConcept C126322002 @default.
• W4308407188 hasConcept C127561419 @default.
• W4308407188 hasConcept C150194340 @default.
• W4308407188 hasConcept C170493617 @default.
• W4308407188 hasConcept C193419808 @default.
• W4308407188 hasConcept C203014093 @default.
• W4308407188 hasConcept C2776914184 @default.
• W4308407188 hasConcept C2777701055 @default.
• W4308407188 hasConcept C2778468042 @default.
• W4308407188 hasConcept C2779282312 @default.
• W4308407188 hasConcept C2779733811 @default.
• W4308407188 hasConcept C2780352672 @default.
• W4308407188 hasConcept C2780851360 @default.
• W4308407188 hasConcept C502942594 @default.
• W4308407188 hasConcept C55493867 @default.
• W4308407188 hasConcept C71924100 @default.
• W4308407188 hasConcept C86803240 @default.
• W4308407188 hasConcept C8891405 @default.
• W4308407188 hasConceptScore W4308407188C104317684 @default.
• W4308407188 hasConceptScore W4308407188C121608353 @default.
• W4308407188 hasConceptScore W4308407188C126322002 @default.
• W4308407188 hasConceptScore W4308407188C127561419 @default.
• W4308407188 hasConceptScore W4308407188C150194340 @default.
• W4308407188 hasConceptScore W4308407188C170493617 @default.
• W4308407188 hasConceptScore W4308407188C193419808 @default.
• W4308407188 hasConceptScore W4308407188C203014093 @default.
• W4308407188 hasConceptScore W4308407188C2776914184 @default.
• W4308407188 hasConceptScore W4308407188C2777701055 @default.
• W4308407188 hasConceptScore W4308407188C2778468042 @default.
• W4308407188 hasConceptScore W4308407188C2779282312 @default.
• W4308407188 hasConceptScore W4308407188C2779733811 @default.
• W4308407188 hasConceptScore W4308407188C2780352672 @default.
• W4308407188 hasConceptScore W4308407188C2780851360 @default.
• W4308407188 hasConceptScore W4308407188C502942594 @default.
• W4308407188 hasConceptScore W4308407188C55493867 @default.
• W4308407188 hasConceptScore W4308407188C71924100 @default.
• W4308407188 hasConceptScore W4308407188C86803240 @default.
• W4308407188 hasConceptScore W4308407188C8891405 @default.
• W4308407188 hasLocation W43084071881 @default.
• W4308407188 hasOpenAccess W4308407188 @default.
• W4308407188 hasPrimaryLocation W43084071881 @default.
• W4308407188 hasRelatedWork W2329974159 @default.
• W4308407188 hasRelatedWork W2401633149 @default.
• W4308407188 hasRelatedWork W2899537551 @default.
• W4308407188 hasRelatedWork W3136031961 @default.
• W4308407188 hasRelatedWork W3174769180 @default.
• W4308407188 hasRelatedWork W3177607563 @default.
• W4308407188 hasRelatedWork W4281759495 @default.
• W4308407188 hasRelatedWork W4293194630 @default.
• W4308407188 hasRelatedWork W4311194928 @default.
• W4308407188 hasRelatedWork W4313369199 @default.
• W4308407188 isParatext "false" @default.
• W4308407188 isRetracted "false" @default.
• W4308407188 workType "article" @default.