Abstract: TH-PO1141
DNA Damage Response Promotes Checkpoint-Specific Upregulation of PVR, CD47, and PD-L1 Through Distinct Regulatory Mechanisms in Kidney Embryonic Cells
Session Information
- Onconephrology: Emerging Biomarkers, Preclinical Models, Clinical Challenges, and Therapeutic Strategies
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Onconephrology
- 1600 Onconephrology
Authors
- Dranitzki Elhalel, Michal, Hadassah University Medical Center, Jerusalem, Jerusalem District, Israel
- Ghantous, Lucy, Hadassah University Medical Center, Jerusalem, Jerusalem District, Israel
- Rachmile, Jacob, Hadassah University Medical Center, Jerusalem, Jerusalem District, Israel
Background
Genotoxic stress is a common feature of cancer that activates the DNA damage response (DDR). Yet, how DDR signaling regulate immune checkpoint (IC) expression, remains incompletely defined. Here, we investigated whether DDR activation coordinately regulates multiple IC ligands.
Methods
Following γ-irradiation and other DNA-damaging agents (Ara-C, Cisplatin or hydrogen peroxide) we quantified cell-surface expression of PD-L1 and the poliovirus receptor PVR (CD155) on human embryonic kidney 293T cell line (HEK-293T; ATCC; CRL-3216) and various other human cells lines by flow cytometry and related these changes to residual γH2AX and to our previous findings relating CD47. In some experiments inhibitors of specific pathways related to DDR were added. mRNA quantified byqRT-PCR. Lentiviral vecters were used to produce HEK-293T Mre-11 shRNA knockdown cells.
Results
DDR activation induced a dose-dependent increase in PD-L1 and PVR surface expression that positively correlated with both γH2AX and CD47 expression levels. Mechanistically, not all ICs tested revealed an identical response. Like CD47, PD-L1 upregulation was accompanied by increased mRNA, whereas PVR induction occurred without detectable transcriptional changes, indicating distinct regulatory modes. Time-course analyses revealed divergent kinetics: PVR and CD47 peaked within 24 hours and declined with DNA damage resolution, while PD-L1 induction was more sustained. Significantly, similar to CD47, PVR appear tightly linked to Mre11’s canonical DNA damage signaling, whereas PD-L1 induction may involve Mre11-independent or compensatory DDR pathways. While acute enzymatic inhibition of Mre11 with mirin suppressed the upregulation of PVR, CD47, and PD-L1, Mre11 silencing using shRNA abrogated only PVR and CD47 induction but not PD-L1.
Conclusion
Together, these findings identify DDR-dependent, non-uniform, checkpoint-specific regulatory programs that may contribute to tumor immune escape following genotoxic therapies and might add considerations to be taken when designing treatment protocols combining irradiation and chemotherapies with immunotherapy, including to renal cell cancers.
Funding
- Commercial Support – KAHR MEDICAL LTD