51P DNA damage ATR/Chk1 checkpoint signalling increases PD-L1 immune checkpoint activation and its implication for personalised combination therapy (Record no. 83454)
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| fixed length control field | 03221nab a22002777a 4500 |
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| 100 ## - MAIN ENTRY--PERSONAL NAME | |
| Personal name | Kumar N |
| 245 ## - TITLE STATEMENT | |
| Title | 51P DNA damage ATR/Chk1 checkpoint signalling increases PD-L1 immune checkpoint activation and its implication for personalised combination therapy |
| 260 ## - PUBLICATION, DISTRIBUTION, ETC. (IMPRINT) | |
| Date of publication, distribution, etc | 2018 |
| 300 ## - PHYSICAL DESCRIPTION | |
| Extent | |
| 500 ## - GENERAL NOTE | |
| General note | Abstract published in the Book of Molecular Analysis for Personalised Therapy (MAP) 2018 14–15 September, Paris, France |
| 520 ## - SUMMARY, ETC. | |
| Summary, etc | Background: DNA double-strand break (DSB) is the most critical type of genotoxic stress. Clinical studies have revealed a link between genomic instability and response to anti-PD-1/PD-L1 therapy in cancer management. We investigated role of DBS repair and ATR/Chk1 DNA damage checkpoint in regulating PD-L1 expression and their use in therapy selection and study design. Methods: Protein expression data proteins and phosphoproteins with major clinical outcome endpoints were obtained from The Cancer Genome Atlas project. A statistical correlation analysis was performed between the expression and distribution DBS repair and ATR/Chk1 DNA damage checkpoint pathway and PD-L1. Signaling network was also analysed for of therapeutic target identification. Results: The expression and distribution patterns of PD-L1 was measured in 7694 samples from 32 cancer type. Increased expression of PD-L1 was associated with higher tumor stage and grade. Analyses of the DNA damage ATR/Chk1 checkpoint signalling revealed strong correlation of PDL1 expression. PD-L1 expression in was upregulated in response to DSBs with strong correlation with MRE11 (correlation coefficient (r) =0.39, p < 0.01), RAD51 (r = 0.33, p < 0.01). This upregulation requires ATM/ATR/Chk1 kinases (Chk2_pt68; r = 0.36, p < 0.01 and Chk1_ps296; r = 0.33, p < 0.01). Interestingly Jab-1 expression was corelated with both Chk-1(r = 0.27, p < 0.01) and PD-L1 (r = 0.22, p < 0.01). We further investigate for the possible signaling mechanism for the correlation and found activation of oncogenic signaling in a cancer type specific manner. PI3K/AKT/mTOR/S6K, INFgamma/ JAK/STAT/IRF1 and Ras/BRAF/MEK/ERK were involved in mechanism of increased PD-L1 expression. Conclusions: DSB-mediated immune activation is balanced by concomitant inhibitory signaling, via the checkpoint kinases ATM, ATR, and Chk1 drived PD-L1 expression in tumors. These observations have important clinical implications for therapy selection, particularly following progression on DNA damaging agents suggesting that PD-1/PD-L1 inhibitors may be a useful therapeutic strategy (with or without concurrent DNA damaging agents) for tumors. |
| 650 ## - SUBJECT ADDED ENTRY--TOPICAL TERM | |
| Topical term or geographic name as entry element | Signal transduction |
| 650 ## - SUBJECT ADDED ENTRY--TOPICAL TERM | |
| Topical term or geographic name as entry element | Combined modality therapy |
| 650 ## - SUBJECT ADDED ENTRY--TOPICAL TERM | |
| Topical term or geographic name as entry element | DNA damage |
| 650 ## - SUBJECT ADDED ENTRY--TOPICAL TERM | |
| Topical term or geographic name as entry element | Cell cycle checkpoint |
| 650 ## - SUBJECT ADDED ENTRY--TOPICAL TERM | |
| Topical term or geographic name as entry element | Programmed cell death 1 ligand 1 |
| 700 ## - ADDED ENTRY--PERSONAL NAME | |
| Personal name | Yadav P |
| 700 ## - ADDED ENTRY--PERSONAL NAME | |
| Personal name | Kumar A |
| 700 ## - ADDED ENTRY--PERSONAL NAME | |
| Personal name | Beniwal S |
| 700 ## - ADDED ENTRY--PERSONAL NAME | |
| Personal name | Kapoor A |
| 700 ## - ADDED ENTRY--PERSONAL NAME | |
| Personal name | Kalwar A |
| 773 ## - HOST ITEM ENTRY | |
| Main entry heading | Annals of oncology |
| Place, publisher, and date of publication | London : Oxford University Press, 2018 |
| Relationship information | Vol.29, no. Suppl_6, mdy315.001 |
| International Standard Serial Number | 0923-7534 |
| 906 ## - LOCAL DATA ELEMENT F, LDF (RLIN) | |
| Dept | Medical Oncology |
| Corporate name | TMC |
| Article Type | Conference Abstract |
| Country type | International |
| Added Entry | TMH |
| 942 ## - ADDED ENTRY ELEMENTS (KOHA) | |
| Item type | Articles |
| Withdrawn status | Lost status | Source of classification or shelving scheme | Damaged status | Not for loan | Permanent location | Current location | Date acquired | Barcode | Date last seen | Koha item type |
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| Tata Memorial Hospital | Tata Memorial Hospital | 2018-12-12 | AR19254 | 2018-12-12 | Articles |