Functional engagement of the PD-1/PD-L1 complex but not PD-L1 expression is highly predictive of patient response to immunotherapy in non-small-cell lung cancer.
Creators: name: Sánchez-Magraner, Lissete
name: Gumuzio, Juan
name: Miles, James
name: Quimi, Nicole
name: Del Prado, Purificación Martínez
name: Abad-Villar, María Teresa
name: Pikabea, Fernando
name: Ortega, Laura
name: Etxezarraga, Carmen
name: Martín-Algarra, Salvador
name: Lozano, María D
name: Saiz-Camin, Mónica
name: Egurrola-Izquierdo, Mikel
name: Barredo-Santamaría, Inmaculada
name: Saiz-López, Alberto
name: Gomez-Mediavilla, Jenifer
name: Segues-Merino, Nerea
name: Juaristi-Abaunz, María Aranzazu
name: Urruticoechea, Ander
name: Geraedts, Erica J
name: van Elst, Kim
name: Claessens, Niels JM
name: Italiano, Antoine
name: Applebee, Christopher J
name: del Castillo, Sandra
name: Evans, Charles
name: Aguirre, Fernando
name: Parker, Peter J
name: Calleja, Véronique
Publisher: name: The Francis Crick Institute
Year: 2023
Subjects: Biochemistry &amp; Proteomics
Signalling &amp; Oncogenes
Cell Biology
Cell Cycle &amp; Chromosomes
Chemical Biology &amp; High Throughput

description: PURPOSE: In many cancers, the expression of immunomodulatory ligands leads to immunoevasion, as exemplified by the interaction of PD-L1 with PD-1 on tumor-infiltrating lymphocytes. Profound advances in cancer treatments have come with the advent of immunotherapies directed at blocking these immuno-suppressive ligand-receptor interactions. However, although there has been success in the use of these immune checkpoint interventions, correct patient stratification for these therapies has been challenging. MATERIALS AND METHODS: To address this issue of patient stratification, we have quantified the intercellular PD-1/PD-L1 interaction in formalin-fixed paraffin-embedded tumor samples from patients with non-small cell lung carcinoma, using a high-throughput automated quantitative imaging platform (quantitative functional proteomics [QF-Pro]). RESULTS: The multisite blinded analysis across a cohort of 188 immune checkpoint inhibitor-treated patients demonstrated the intra- and intertumoral heterogeneity of PD-1/PD-L1 immune checkpoint engagement and notably showed no correlation between the extent of PD-1/PD-L1 interaction and PD-L1 expression. Importantly, PD-L1 expression scores used clinically to stratify patients correlated poorly with overall survival; by contrast, patients showing a high PD-1/PD-L1 interaction had significantly better responses to anti-PD-1/PD-L1 treatments, as evidenced by increased overall survival. This relationship was particularly strong in the setting of first-line treatments. CONCLUSION: The functional readout of PD-1/PD-L1 interaction as a predictive biomarker for the stratification of patients with non-small-cell lung carcinoma, combined with PD-L1 expression, should significantly improve the response rates to immunotherapy. This would both capture patients excluded from checkpoint immunotherapy (high PD-1/PD-L1 interaction but low PD-L1 expression, 24% of patients) and additionally avoid treating patients who despite their high PD-L1 expression do not respond and suffer from side effects.