Juaristi-Abaunz, M.A. (María Aranzazu)

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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
    (2023) Juaristi-Abaunz, M.A. (María Aranzazu); Gumuzio, J. (Juan); Urruticoechea, A. (Ander); Barredo-Santamaria, I. (Inmaculada); Italiano, A. (Antoine); Lozano, M.D. (María Dolores); Saiz-Camin, M. (Mónica); Claessens, N.J.M. (Niels J. M.); Geraedts, E.J. (Erica J.); Martinez-del-Prado, P. (Purificación); Martin-Algarra, S. (Salvador); Sanchez-Magraner, L. (Lissete); Elst, K. (Kim) van; Ortega, L. (Laura); Quimi, N. (Nicole); Egurrola-Izquierdo, M. (Mikel); Miles, J. (James); Calleja, V. (Veronique); Abad-Villar, M.T. (María Teresa); Segues-Merino, N. (Nerea); Gomez-Mediavilla, J. (Jenifer); Aguirre, F. (Fernando); Pikabea, F. (Fernando); Parker, C. (Charles); Applebee, C.J. (Christopher J.); Saiz-Lopez, A. (Alberto); Etxezarraga, C. (Carmen); Evans, C. (Charles); Castillo, S. (Sandra) del
    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.