51P DNA damage ATR/Chk1 checkpoint signalling increases PD-L1 immune checkpoint activation and its implication for personalised combination therapy (Record no. 83454)

000 -LEADER
fixed length control field 03221nab a22002777a 4500
008 - FIXED-LENGTH DATA ELEMENTS--GENERAL INFORMATION
fixed length control field 181212b xxu||||| |||| 00| 0 eng d
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
Holdings
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
          Tata Memorial Hospital Tata Memorial Hospital 2018-12-12 AR19254 2018-12-12 Articles

Powered by Koha