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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.

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posted on 2023-05-11, 09:30 authored by Lissete Sánchez-Magraner, Juan Gumuzio, James Miles, Nicole Quimi, Purificación Martínez Del Prado, María Teresa Abad-Villar, Fernando Pikabea, Laura Ortega, Carmen Etxezarraga, Salvador Martín-Algarra, María D Lozano, Mónica Saiz-Camin, Mikel Egurrola-Izquierdo, Inmaculada Barredo-Santamaría, Alberto Saiz-López, Jenifer Gomez-Mediavilla, Nerea Segues-Merino, María Aranzazu Juaristi-Abaunz, Ander Urruticoechea, Erica J Geraedts, Kim van Elst, Niels JM Claessens, Antoine Italiano, Christopher J Applebee, Sandra del Castillo, Charles Evans, Fernando Aguirre, Peter J Parker, Véronique Calleja
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.

Funding

Crick (Grant ID: CC2140, Grant title: Parker CC2140)

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