In Situ Detection of Programmed Cell Death Protein 1 and Programmed Death Ligand 1 Interactions as a Functional...

Area of Science:

• Oncology
• Immunology
• Biomarker Discovery

Background:

• Immune checkpoint inhibitors (ICIs) have revolutionized lung cancer therapy but show variable efficacy.
• Current biomarkers like programmed death ligand 1 (PD-L1) expression have limited predictive power.
• Assessing direct programmed cell death protein 1 (PD1)-PD-L1 interactions may offer superior prediction of treatment response.

Purpose of the Study:

• To evaluate the utility of detecting PD1-PD-L1 interactions as a biomarker for ICI treatment in various cancers.
• To compare the predictive value of PD1-PD-L1 interactions with standard PD-L1 expression assays.
• To identify mechanisms of ICI resistance in non-responding patients.

Main Methods:

• A proximity ligation assay was used to detect PD1-PD-L1 interactions in diagnostic samples from 16 cancer types.
• Analysis included early-stage and advanced non-small cell lung cancer (NSCLC) patient cohorts, with and without ICI treatment.
• RNA sequencing was employed to investigate resistance mechanisms.

Main Results:

• PD1-PD-L1 interactions were detected in a subset of NSCLC cases with PD-L1 and PD1 expression, with lower levels in EGFR-mutated tumors.
• Higher PD1-PD-L1 interaction levels correlated with complete response and improved survival in ICI-treated NSCLC patients.
• Non-responders with high interactions showed additional expression of immune mediators like EOMES and HAVCR1.

Conclusions:

• Assessing active immune pathways via PD1-PD-L1 interactions provides more precise ICI treatment guidance than static biomarker quantification.
• This functional diagnostic approach is applicable to small biopsies and can be extended to other immune checkpoints.
• Findings suggest combined diagnostic and therapeutic strategies are needed to overcome ICI resistance.