TY  - JOUR
AU  - Ghantous, Lucy
AU  - Volman, Yael
AU  - Hefez, Ruth
AU  - Wald, Ori
AU  - Stern, Esther
AU  - Friehmann, Tomer
AU  - Chajut, Ayelet
AU  - Bremer, Edwin
AU  - Elhalel, Michal Dranitzki
AU  - Rachmilewitz, Jacob
TI  - The DNA damage response pathway regulates the expression of the immune checkpoint CD47.
JO  - Communications biology
VL  - 6
IS  - 1
SN  - 2399-3642
CY  - London
PB  - Springer Nature
M1  - DKFZ-2025-02411
SP  - 245
PY  - 2023
N1  - #DKFZ-MOST-Ca182#
AB  - CD47 is a cell surface ligand expressed on all nucleated cells. It is a unique immune checkpoint protein acting as 'don't eat me' signal to prevent phagocytosis and is constitutively overexpressed in many tumors. However, the underlying mechanism(s) for CD47 overexpression is not clear. Here, we show that irradiation (IR) as well as various other genotoxic agents induce elevated expression of CD47. This upregulation correlates with the extent of residual double-strand breaks (DSBs) as determined by γH2AX staining. Interestingly, cells lacking mre-11, a component of the MRE11-RAD50-NBS1 (MRN) complex that plays a central role in DSB repair, or cells treated with the mre-11 inhibitor, mirin, fail to elevate the expression of CD47 upon DNA damage. On the other hand, both p53 and NF-κB pathways or cell-cycle arrest do not play a role in CD47 upregualtion upon DNA damage. We further show that CD47 expression is upregulated in livers harvested from mice treated with the DNA-damage inducing agent Diethylnitrosamine (DEN) and in cisplatin-treated mesothelioma tumors. Hence, our results indicate that CD47 is upregulated following DNA damage in a mre-11-dependent manner. Chronic DNA damage response in cancer cells might contribute to constitutive elevated expression of CD47 and promote immune evasion.
KW  - Animals
KW  - Mice
KW  - CD47 Antigen: genetics
KW  - Cell Membrane
KW  - Cell Nucleus
KW  - DNA Damage
KW  - Liver
KW  - CD47 Antigen (NLM Chemicals)
KW  - Cd47 protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:36882648
C2  - pmc:PMC9992352
DO  - DOI:10.1038/s42003-023-04615-6
UR  - https://inrepo02.dkfz.de/record/305794
ER  -