FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4308394673> ?p ?o ?g. }

• W4308394673 abstract "<h3>Background</h3> Tumor PDL1 signals extrinsically to immune cell PD1 to evade antitumor immunity and is highly expressed on distinct cancers.^1-7 Aside from tumor-extrinsic functions, we and others discovered various pathologic tumor-intrinsic PDL1 signals in distinct cancers, including melanoma.^{2 7 8} We found that melanocytes (the melanoma cell-of-origin) do not express PDL1 but exhibit a gradual progression of PDL1 expression as cells transform from benign nevi to malignant melanomas, suggesting a role for PDL1 in melanomagenesis. We now investigate melanocyte-intrinsic PDL1 signaling, to distinguish bona-fide PDL1 signaling influence on melanomagenesis in the absence of potentially confounding compensatory mechanisms in prior genetic PDL1^KO studies in established tumors. We hypothesized that melanocyte-intrinsic PDL1 signals drive melanomagenesis and progression through immune and non-immune mechanisms. <h3>Methods</h3> To test melanocyte-intrinsic PDL1 signals during melanomagenesis, we developed an autochthonous, tamoxifen-inducible, UV accelerated, Nras-driven mouse model where mice develop melanomas that are Nras^Q61R mutant and lack PDL1 specifically only in melanocytes versus littermates. Mice were induced with tamoxifen on post-natal days 2-3 ± distinct UV exposures and monitored for tumor growth. We established transplantable cell lines from derived tumors and SQ challenged into WT BL6 mice for in vivo treatment studies and studied PDL1 signaling in vitro. <h3>Results</h3> Melanocyte PDL1 promotes melanomagenesis in a UV dose-dependent manner. Tumor latency was significantly increased in PDL1^KO TN^Q61R mice versus littermates at 2 kJ/m² UV (p<0.02) suggesting an immune latency contribution. At 4.5 kJ/m² UV, PDL1^KO TN^Q61Rversus littermate melanoma latencies were indistinguishable, but faster than respective cohorts at 2 kJ/m² possibly from immunosuppression at higher UV doses. Genetic PDL1^KO in B16 melanoma induces synthetic lethality to small molecule Chk1 inhibitors by destabilizing Chk2 protein through increased ubiquitination, an effect phenocopied in vitro and in vivo in tumors from PDL1^KO TN^Q61Rversus littermates. Tumors from PDL1^KO TN^Q61Rversus littermates transplanted into WT recipients were resistant to αPD1, αPDL1, αPDL2, and CD122-biased IL2 immunotherapies, differing from B16 melanomas that are sensitive to all these treatments. Notably, tumor PDL1 suppresses ERK signaling, a downstream target of Nras, in TN^Q61R cell lines, suggesting PDL1 control of Nras-mediated oncogenesis. <h3>Conclusions</h3> Our novel model dissociates bona-fide cell-intrinsic PDL1 signals from potential genetic PDL1^KO compensation confounding effects, allows studies of earliest PDL1 signals in melanomagenesis and progression, helps understand if PDL1 affects Nras-driven oncogenesis, and helps test immunotherapy and small molecule treatment effects. A parallel bladder cancer model was also developed, to be reported later. <h3>Acknowledgements</h3> This research was funded by the NIH T32GM113896 (STX MSTP) Award (C.O.). The Clayton Foundation (no grant number) and the NCI (CA204965, CA054515) supported Curiel. <h3>References</h3> Clark CA, Gupta HB, Curiel TJ: Tumor cell-intrinsic CD274/PD-L1: A novel metabolic balancing act with clinical potential. <i>Autophagy</i> 2017;<b>13</b>(5):987-988. Clark CA, Gupta HB, Sareddy G, Pandeswara S, Lao S, Yuan B, Drerup JM, Padron A, Conejo-Garcia J, Murthy K, <i>et al</i>: Tumor-Intrinsic PD-L1 Signals Regulate Cell Growth, Pathogenesis, and Autophagy in Ovarian Cancer and Melanoma. <i>Cancer Res</i> 2016;<b>76</b>(23):6964-6974. Gupta HB, Murray C, Deng J, Mohammad TAS, Zhang X, Wu B, Clark C, Sareddy G, Chen Y, Vadlamudi R, <i>et al</i>: Tumor-intrinsic PD-L1 regulates tumor initiating cell virulence and stemness genes, and TCF1+ stem-like T cells through Raptor in ovarian cancer, which correlates with survival in high grade serous ovarian cancer. <i>Journal of Immunology</i> 2019;<b>202</b>:195.129. Kornepati AV, Zhang D, Padron AS, Boyd JT, Deng Y, Osta EG, Reyes RM, Shen H, Wang J, Kari S, <i>et al</i>: Tumor cell-intrinsic PD-L1 signals promote DNA damage responses that mediate resistance to Chk1 and PARP inhibitors in vivo. <i>Journal of Immunology</i> 2020;<b>204</b>:241.233. Hambright HG, Gupta HB, Padrón Á, Vadlamudi R, Chen Y, Osmulski PA, Curiel TJ: Surface and cytoplasmic tumor cell PD-L1 differentially mediate virulence in ovarian cancer and melanoma through mTOR activation. <i>Journal of Immunology</i> 2019;<b>202</b>:195.195. Kornepati AVR, Boyd JT, Murray CE, Saifetyarova J, de la Pena Avalos B, Rogers CM, Bai H, Padron AS, Liao Y, Ontiveros C, <i>et al</i>: Tumor-intrinsic PD-L1 promotes DNA repair in distinct cancers and suppresses PARP inhibitor-induced synthetic lethality. <i>Cancer Res</i> 2022;<b>82</b>(11):2156-2170. Kornepati AVR, Vadlamudi RK, Curiel TJ: Programmed death ligand 1 signals in cancer cells. <i>Nat Rev Cancer</i> 2022;<b>22</b>(3):174-189. Gupta HB, Clark CA, Yuan B, Sareddy G, Pandeswara S, Padron AS, Hurez V, Conejo-Garcia J, Vadlamudi R, Li R, <i>et al</i>: Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation and functions in melanoma and ovarian cancer. <i>Signal Transduct Target Ther</i> 2016;<b>1</b>(1):1-9. <h3>Ethics Approval</h3> All animal studies were approved by the UT Health San Antonio Institutional Animal Care and Use Committee and each experiment was conducted in accordance with the standards required by the UT Health San Antonio Department of Laboratory Animal Resources. Approval number: 09128" @default.
• W4308394673 created "2022-11-11" @default.
• W4308394673 creator A5017130108 @default.
• W4308394673 creator A5044217766 @default.
• W4308394673 creator A5045824377 @default.
• W4308394673 creator A5062517303 @default.
• W4308394673 creator A5070479090 @default.
• W4308394673 creator A5074770263 @default.
• W4308394673 creator A5079368617 @default.
• W4308394673 creator A5089219799 @default.
• W4308394673 date "2022-11-01" @default.
• W4308394673 modified "2023-09-25" @default.
• W4308394673 title "1428 Melanocyte-intrinsic PDL1 promotes tumorigenesis and progression in a novel autochthonous melanoma model" @default.
• W4308394673 doi "https://doi.org/10.1136/jitc-2022-sitc2022.1428" @default.
• W4308394673 hasPublicationYear "2022" @default.
• W4308394673 type Work @default.
• W4308394673 citedByCount "0" @default.
• W4308394673 crossrefType "proceedings-article" @default.
• W4308394673 hasAuthorship W4308394673A5017130108 @default.
• W4308394673 hasAuthorship W4308394673A5044217766 @default.
• W4308394673 hasAuthorship W4308394673A5045824377 @default.
• W4308394673 hasAuthorship W4308394673A5062517303 @default.
• W4308394673 hasAuthorship W4308394673A5070479090 @default.
• W4308394673 hasAuthorship W4308394673A5074770263 @default.
• W4308394673 hasAuthorship W4308394673A5079368617 @default.
• W4308394673 hasAuthorship W4308394673A5089219799 @default.
• W4308394673 hasBestOaLocation W43083946731 @default.
• W4308394673 hasConcept C121608353 @default.
• W4308394673 hasConcept C203014093 @default.
• W4308394673 hasConcept C21790070 @default.
• W4308394673 hasConcept C2777658100 @default.
• W4308394673 hasConcept C2779256057 @default.
• W4308394673 hasConcept C2779769559 @default.
• W4308394673 hasConcept C2781187634 @default.
• W4308394673 hasConcept C502942594 @default.
• W4308394673 hasConcept C526805850 @default.
• W4308394673 hasConcept C54355233 @default.
• W4308394673 hasConcept C555283112 @default.
• W4308394673 hasConcept C86803240 @default.
• W4308394673 hasConcept C8891405 @default.
• W4308394673 hasConceptScore W4308394673C121608353 @default.
• W4308394673 hasConceptScore W4308394673C203014093 @default.
• W4308394673 hasConceptScore W4308394673C21790070 @default.
• W4308394673 hasConceptScore W4308394673C2777658100 @default.
• W4308394673 hasConceptScore W4308394673C2779256057 @default.
• W4308394673 hasConceptScore W4308394673C2779769559 @default.
• W4308394673 hasConceptScore W4308394673C2781187634 @default.
• W4308394673 hasConceptScore W4308394673C502942594 @default.
• W4308394673 hasConceptScore W4308394673C526805850 @default.
• W4308394673 hasConceptScore W4308394673C54355233 @default.
• W4308394673 hasConceptScore W4308394673C555283112 @default.
• W4308394673 hasConceptScore W4308394673C86803240 @default.
• W4308394673 hasConceptScore W4308394673C8891405 @default.
• W4308394673 hasLocation W43083946731 @default.
• W4308394673 hasOpenAccess W4308394673 @default.
• W4308394673 hasPrimaryLocation W43083946731 @default.
• W4308394673 hasRelatedWork W1663620072 @default.
• W4308394673 hasRelatedWork W1980427440 @default.
• W4308394673 hasRelatedWork W2028752124 @default.
• W4308394673 hasRelatedWork W2159633569 @default.
• W4308394673 hasRelatedWork W2476596138 @default.
• W4308394673 hasRelatedWork W2613470058 @default.
• W4308394673 hasRelatedWork W2787582709 @default.
• W4308394673 hasRelatedWork W2964616224 @default.
• W4308394673 hasRelatedWork W3112004363 @default.
• W4308394673 hasRelatedWork W3129743340 @default.
• W4308394673 isParatext "false" @default.
• W4308394673 isRetracted "false" @default.
• W4308394673 workType "article" @default.