High PD-1/PD-L1 Checkpoint Interaction Infers Tumor Selection and Therapeutic Sensitivity to Anti-PD-1/PD-L1 Treatment.

Autor:	Sánchez-Magraner L; FASTBASE Solutions S.L, Astondo bidea, Derio, Spain., Miles J; FASTBASE Solutions S.L, Astondo bidea, Derio, Spain.; Cell Biophysics Laboratory, Ikerbasque, Basque Foundation for Science, Research Centre for Experimental Marine Biology and Biotechnology (PiE) & Biophysics Institute (UPV/EHU, CSIC), University of the Basque Country, Leioa, Biscay, Spain.; Centre for Therapeutic Innovation, Cell Biophysics Laboratory, Department of Pharmacy and Pharmacology, & Department of Physics, University of Bath, Claverton Down, Bath, United Kingdom.; Early Phase Trials and Sarcoma, Institut Bergonié, Cours de l'Argonne, Bordeaux, France., Baker CL; Cell Biophysics Laboratory, Ikerbasque, Basque Foundation for Science, Research Centre for Experimental Marine Biology and Biotechnology (PiE) & Biophysics Institute (UPV/EHU, CSIC), University of the Basque Country, Leioa, Biscay, Spain., Applebee CJ; FASTBASE Solutions S.L, Astondo bidea, Derio, Spain.; Cell Biophysics Laboratory, Ikerbasque, Basque Foundation for Science, Research Centre for Experimental Marine Biology and Biotechnology (PiE) & Biophysics Institute (UPV/EHU, CSIC), University of the Basque Country, Leioa, Biscay, Spain.; Centre for Therapeutic Innovation, Cell Biophysics Laboratory, Department of Pharmacy and Pharmacology, & Department of Physics, University of Bath, Claverton Down, Bath, United Kingdom., Lee DJ; Basque Centre for Applied Mathematics, Bilbao, Bizkaia, Spain., Elsheikh S; Department of Cellular Pathology, Queens Medical Centre, Nottingham, United Kingdom., Lashin S; Department of Cellular Pathology, Queens Medical Centre, Nottingham, United Kingdom., Withers K; Cell Biophysics Laboratory, Ikerbasque, Basque Foundation for Science, Research Centre for Experimental Marine Biology and Biotechnology (PiE) & Biophysics Institute (UPV/EHU, CSIC), University of the Basque Country, Leioa, Biscay, Spain., Watts AG; Bath ASU, Corsham, United Kingdom., Parry R; Bath ASU, Corsham, United Kingdom., Edmead C; Centre for Therapeutic Innovation, Cell Biophysics Laboratory, Department of Pharmacy and Pharmacology, & Department of Physics, University of Bath, Claverton Down, Bath, United Kingdom.; Leukocyte Biology Laboratory, Centre for Therapeutic Innovation & Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, United Kingdom., Lopez JI; Department of Pathology, Cruces University Hospital, Biocruces Research Institute, Barakaldo, Bizkaia, Spain., Mehta R; Apple Tree Partners, London, United Kingdom., Italiano A; Early Phase Trials and Sarcoma, Institut Bergonié, Cours de l'Argonne, Bordeaux, France., Ward SG; Leukocyte Biology Laboratory, Centre for Therapeutic Innovation & Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, United Kingdom., Parker PJ; Protein Phosphorylation Laboratory, The Francis Crick Institute, London, United Kingdom. bl666@bath.ac.uk peter.parker@crick.ac.uk.; School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom., Larijani B; FASTBASE Solutions S.L, Astondo bidea, Derio, Spain. bl666@bath.ac.uk peter.parker@crick.ac.uk.; Cell Biophysics Laboratory, Ikerbasque, Basque Foundation for Science, Research Centre for Experimental Marine Biology and Biotechnology (PiE) & Biophysics Institute (UPV/EHU, CSIC), University of the Basque Country, Leioa, Biscay, Spain.; Centre for Therapeutic Innovation, Cell Biophysics Laboratory, Department of Pharmacy and Pharmacology, & Department of Physics, University of Bath, Claverton Down, Bath, United Kingdom.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2020 Oct 01; Vol. 80 (19), pp. 4244-4257. Date of Electronic Publication: 2020 Aug 27.
DOI:	10.1158/0008-5472.CAN-20-1117
Abstrakt:	Many cancers are termed immunoevasive due to expression of immunomodulatory ligands. Programmed death ligand-1 (PD-L1) and cluster of differentiation 80/86 (CD80/86) interact with their receptors, programmed death receptor-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4), respectively, on tumor-infiltrating leukocytes eliciting immunosuppression. Immunotherapies aimed at blocking these interactions are revolutionizing cancer treatments, albeit in an inadequately described patient subset. To address the issue of patient stratification for immune checkpoint intervention, we quantitatively imaged PD-1/PD-L1 interactions in tumor samples from patients, employing an assay that readily detects these intercellular protein-protein interactions in the less than or equal to 10 nm range. These analyses across multiple patient cohorts demonstrated the intercancer, interpatient, and intratumoral heterogeneity of interacting immune checkpoints. The PD-1/PD-L1 interaction was not correlated with clinical PD-L1 expression scores in malignant melanoma. Crucially, among anti-PD-1-treated patients with metastatic non-small cell lung cancer, those with lower PD-1/PD-L1 interaction had significantly worsened survival. It is surmised that within tumors selecting for an elevated level of PD-1/PD-L1 interaction, there is a greater dependence on this pathway for immune evasion and hence, they exhibit more impressive patient response to intervention. SIGNIFICANCE: Quantitation of immune checkpoint interaction by direct imaging demonstrates that immunotherapy-treated patients with metastatic NSCLC with a low extent of PD-1/PD-L1 interaction show significantly worse outcome. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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