asco@alo33:170652 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/asco@alo33/sourceid/170652","sourcedb":"asco@alo33","sourceid":"170652","text":" Background: Success of immune checkpoint blockade therapy relies on the increase of effector T cells and decrease of regulatory T cells in the tumor microenvironment. Hoever, the underlying mechanism that govern the ratio of effector and regulatory T cells in response to checkpoint blockade is not understood. Differentiation of naxEF;ve T cells into effector and regulatory phenotype requires lineage-specifying transcription factors and epigenetic modifications that allo appropriate repression or activation of gene transcription. One key epigenetic modification for T cell differentiation is trimethylation of lysine 27 on histone H3 H3K27me3 . Loss of H3K27me3 results in increased Th-1 plasticity hereas presence of H3K27me3 on Foxp3 locus is required to maintain the function of T-regulatory cells. We hypothesize that immune checkpoint blockade changes the epigenetic landscape in tumor infiltrating T cells TILs that results in an effector phenotype and epigenetic modification of H3K27me3 could promote an antitumor immune microenvironment in tumor bearing mice. Methods: To investigate the epigenetic changes in TILs in response to immune checkpoint blockade therapy, ChIP-sequencing ill be performed on TILs derived from B16-F10 melanoma , RENCA renal cell and MB-49 bladder mice model. Further, e ill use the mice models to investigate the combinatorial effect of epigenetic modulation of H3K27me3 and immune checkpoint blockade in the tumor microenvironment. Results: We shoed that in-vivo inhibition of H3K27me3 in combination ith anti-CTLA4 results in reduction of tumor size and also reduction in regulatory T cells in a B16-F10 melanoma mice model compared to anti-CTLA4 treatment alone, suggesting H3K27me3 inhibition could increase the efficacy of checkpoint blockade therapy. Conclusions: Data generated in this project ill greatly enhance our understanding of epigenetic regulation of T cell differentiation is response to immune checkpoint blockade and aid identifying key changes that could be further modified to overcome resistance to immune checkpoint blockade in non-responders.,J Clin Oncol 34, 2016 suppl; abstr 11549 00:00.0,Tumor Biology \n","tracks":[{"project":"ASCO_abstracts","denotations":[{"id":"T1","span":{"begin":145,"end":150},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T2","span":{"begin":893,"end":898},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T3","span":{"begin":1059,"end":1064},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T4","span":{"begin":1248,"end":1256},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T5","span":{"begin":1460,"end":1465},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T6","span":{"begin":1592,"end":1597},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T7","span":{"begin":1657,"end":1665},"obj":"DiseaseOrPhenotypicFeature"}],"attributes":[{"id":"A1","pred":"mondo_id","subj":"T1","obj":"0005070"},{"id":"A2","pred":"mondo_id","subj":"T2","obj":"0005070"},{"id":"A3","pred":"mondo_id","subj":"T3","obj":"0005070"},{"id":"A4","pred":"mondo_id","subj":"T4","obj":"0005105"},{"id":"A5","pred":"mondo_id","subj":"T5","obj":"0005070"},{"id":"A6","pred":"mondo_id","subj":"T6","obj":"0005070"},{"id":"A7","pred":"mondo_id","subj":"T7","obj":"0005105"},{"subj":"T1","pred":"source","obj":"ASCO_abstracts"},{"subj":"T2","pred":"source","obj":"ASCO_abstracts"},{"subj":"T3","pred":"source","obj":"ASCO_abstracts"},{"subj":"T4","pred":"source","obj":"ASCO_abstracts"},{"subj":"T5","pred":"source","obj":"ASCO_abstracts"},{"subj":"T6","pred":"source","obj":"ASCO_abstracts"},{"subj":"T7","pred":"source","obj":"ASCO_abstracts"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"ASCO_abstracts","color":"#ca93ec","default":true}]}]}}