| http://purl.uniprot.org/citations/33771897 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/33771897 | http://www.w3.org/2000/01/rdf-schema#comment | "Current clinical trials of combined EGFR-tyrosine kinase inhibitors (TKI) and immune checkpoint blockade (ICB) therapies show no additional effect. This raises questions regarding whether EGFR-TKIs attenuate ICB-enhanced CD8+ T lymphocyte function. Here we show that the EGFR-TKI afatinib suppresses CD8+ T lymphocyte proliferation, and we identify CAD, a key enzyme of de novo pyrimidine biosynthesis, to be a novel afatinib target. Afatinib reduced tumor-infiltrating lymphocyte numbers in Lewis lung carcinoma (LLC)-bearing mice. Early afatinib treatment inhibited CD8+ T lymphocyte proliferation in patients with non-small cell lung cancer, but their proliferation unexpectedly rebounded following long-term treatment. This suggests a transient immunomodulatory effect of afatinib on CD8+ T lymphocytes. Sequential treatment of afatinib with anti-PD1 immunotherapy substantially enhanced therapeutic efficacy in MC38 and LLC-bearing mice, while simultaneous combination therapy showed only marginal improvement over each single treatment. These results suggest that afatinib can suppress CD8+ T lymphocyte proliferation by targeting CAD, proposing a timing window for combined therapy that may prevent the dampening of ICB efficacy by EGFR-TKIs. SIGNIFICANCE: This study elucidates a mechanism of afatinib-mediated immunosuppression and provides new insights into treatment timing for combined targeted therapy and immunotherapy. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/12/3270/F1.large.jpg."xsd:string |
| http://purl.uniprot.org/citations/33771897 | http://purl.org/dc/terms/identifier | "doi:10.1158/0008-5472.can-20-3436"xsd:string |
| http://purl.uniprot.org/citations/33771897 | http://purl.uniprot.org/core/author | "Chang G.D."xsd:string |
| http://purl.uniprot.org/citations/33771897 | http://purl.uniprot.org/core/author | "Lee M.S."xsd:string |
| http://purl.uniprot.org/citations/33771897 | http://purl.uniprot.org/core/author | "Ramon-Maiques S."xsd:string |
| http://purl.uniprot.org/citations/33771897 | http://purl.uniprot.org/core/author | "Lin H.Y."xsd:string |
| http://purl.uniprot.org/citations/33771897 | http://purl.uniprot.org/core/author | "Lin H.H."xsd:string |
| http://purl.uniprot.org/citations/33771897 | http://purl.uniprot.org/core/author | "Lee D.Y."xsd:string |
| http://purl.uniprot.org/citations/33771897 | http://purl.uniprot.org/core/author | "Lee C.F."xsd:string |
| http://purl.uniprot.org/citations/33771897 | http://purl.uniprot.org/core/author | "Lee C.T."xsd:string |
| http://purl.uniprot.org/citations/33771897 | http://purl.uniprot.org/core/author | "Chen I.C."xsd:string |
| http://purl.uniprot.org/citations/33771897 | http://purl.uniprot.org/core/author | "Del Cano-Ochoa F."xsd:string |
| http://purl.uniprot.org/citations/33771897 | http://purl.uniprot.org/core/author | "Ho C.C."xsd:string |
| http://purl.uniprot.org/citations/33771897 | http://purl.uniprot.org/core/author | "Ku C.C."xsd:string |
| http://purl.uniprot.org/citations/33771897 | http://purl.uniprot.org/core/author | "Ko C.J."xsd:string |
| http://purl.uniprot.org/citations/33771897 | http://purl.uniprot.org/core/author | "Lan S.W."xsd:string |
| http://purl.uniprot.org/citations/33771897 | http://purl.uniprot.org/core/author | "Chuang Y.H."xsd:string |
| http://purl.uniprot.org/citations/33771897 | http://purl.uniprot.org/core/author | "Tu H.F."xsd:string |
| http://purl.uniprot.org/citations/33771897 | http://purl.uniprot.org/core/date | "2021"xsd:gYear |
| http://purl.uniprot.org/citations/33771897 | http://purl.uniprot.org/core/name | "Cancer Res"xsd:string |
| http://purl.uniprot.org/citations/33771897 | http://purl.uniprot.org/core/pages | "3270-3282"xsd:string |
| http://purl.uniprot.org/citations/33771897 | http://purl.uniprot.org/core/title | "Afatinib Exerts Immunomodulatory Effects by Targeting the Pyrimidine Biosynthesis Enzyme CAD."xsd:string |
| http://purl.uniprot.org/citations/33771897 | http://purl.uniprot.org/core/volume | "81"xsd:string |
| http://purl.uniprot.org/citations/33771897 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/33771897 |