Publicaciones científicas

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

10-may-2023 | Revista: Journal of Clinical Oncology

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.

CITA DEL ARTÍCULO  J Clin Oncol. 2023 May 10;41(14):2561-2570.
doi: 10.1200/JCO.22.01748. Epub 2023 Feb 23