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
Lissete Sánchez-Magraner 1 , Juan Gumuzio 1 , James Miles 1 , Nicole Quimi 1 , Purificación Martínez Del Prado 2 , María Teresa Abad-Villar 2 , Fernando Pikabea 2 , Laura Ortega 2 , Carmen Etxezarraga 2 , Salvador Martín-Algarra 3 , María D Lozano 3 , Mónica Saiz-Camin 4 , Mikel Egurrola-Izquierdo 5 , Inmaculada Barredo-Santamaría 5 , Alberto Saiz-López 5 , Jenifer Gomez-Mediavilla 6 , Nerea Segues-Merino 6 , María Aranzazu Juaristi-Abaunz 6 , Ander Urruticoechea 6 , Erica J Geraedts 7 , Kim van Elst 7 , Niels J M Claessens 8 , Antoine Italiano 9 , Christopher J Applebee 1 , Sandra Del Castillo 1 10 , Charles Evans 1 , Fernando Aguirre 1 , Peter J Parker 1 11 12 , Véronique Calleja 1
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.
CITATION J Clin Oncol. 2023 May 10;41(14):2561-2570.
doi: 10.1200/JCO.22.01748. Epub 2023 Feb 23