Nuclear PD-L1 triggers tumour-associated inflammation upon DNA damage.

Area of Science:

• Immunology
• Molecular Biology
• Oncology

Background:

• Immune checkpoint inhibitors targeting PD-1/PD-L1 are effective in hot tumors like triple-negative breast cancer.
• Constitutive DNA damage in these tumors promotes inflammation and PD-L1 expression for immune evasion.
• The precise role of PD-L1 in regulating DNA damage response and inflammation remains largely unknown.

Purpose of the Study:

• To investigate the function of PD-L1 in the DNA damage response (DDR) and inflammation.
• To elucidate the molecular mechanisms by which PD-L1 influences the tumor microenvironment.
• To determine if nuclear PD-L1 plays a role in DDR and inflammatory signaling.

Main Methods:

• Investigated PD-L1's interaction with ATR and its role in Chk1 activation and chromatin binding.
• Utilized PD-L1 deletion and inhibitors of ATR/Chk1 to assess their impact on DNA damage response pathways.
• Examined the role of nuclear PD-L1 localization using mutations and inhibitors like Santacruzamate A and C646.
• Assessed the induction of proinflammatory chemocytokines upon genotoxic stress.

Main Results:

• Nuclear PD-L1 activates the ATR-Chk1 pathway, inducing proinflammatory chemocytokines upon genotoxic stress.
• PD-L1 directly interacts with ATR, being essential for Chk1 activation and chromatin binding.
• PD-L1 deletion or ATR/Chk1 inhibition suppresses late-phase cGAS-STING and NF-κB activation and subsequent chemocytokine induction.
• Inhibition of PD-L1 nuclear localization reduces chemocytokine induction, while accelerated localization enhances it.

Conclusions:

• Nuclear PD-L1 acts as a key regulator of the DNA damage response and inflammation.
• PD-L1 strengthens 'hot tumor' properties by modulating the tumor microenvironment.
• Targeting nuclear PD-L1 localization or its interaction with ATR-Chk1 could offer novel therapeutic strategies.