Abstract 1386: 5-FU-induces PD-L1 in the absence of p53 via ATM dependent activation of STAT3

Abstract

Abstract Background: 5-Fluorouracil (5-FU) is an antimetabolite DNA damaging chemotherapeutics that forms the backbone for treatment of colorectal cancer (CRC) and currently it is the most commonly used anti-cancer drug. Despite the central role played by p53 in regulating DNA-damage response, its role in regulating response to 5-FU remains unclear. Methods: To better understand how p53 status differentially affects response to 5-FU, we conducted a detailed phenotypic analysis of the effects of 5FU alone or in combination with Oxaliplatin on cell cycle, DNA damage, cell death, DNA repair and consequent signaling across a panel of p53 isogenic, null and mutant CRC cell lines. Results: This revealed that while 5-FU induce both p53 dependent and independent cell death, the effects on cell cycle are profoundly different, with p53 deficient cells accumulating in S-phase with prolongated double strand breaks. This is not observed in p53 proficient cells, which are protected from these effects by induction of the p53 target gene p21/CDKN1A limiting cell cycle and enforcing suppression of cell cycle genes. Notably in both p53 or p21 deficient cells 5-FU results in sustained DNA damage-signaling through ATR and ATM in p53 deficient cells which preferentially arrest in S-phase. Importantly, these cells exhibit significant induction of cell surface expression of programmed death ligand-1 (PD-L1), which is enhanced by ATR inhibition concomitant with increased ATM activation. Further analysis indicates that transcriptional induction of PD-L1 is mediated through STAT3 in an interferon independent manner. Conclusion: This work adds significantly to our understanding of how p53 status impacts 5FU induced cell cycle arrest and response in CRC patients and have important implications for understanding 5-FU response, particularly in future combinations with immune checkpoint inhibitors. Citation Format: Tamas Sessler, Fiammetta Falcone, Peter Gallagher, Timothy Wright, Kienan Savage, Daniel B. Longley, Simon S. McDade. 5-FU-induces PD-L1 in the absence of p53 via ATM dependent activation of STAT3 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1386.