title: PD-L1 on peripheral blood T lymphocytes is prognostic in patients with non-small cell lung cancer (NSCLC) treated with EGFR inhibitors.
abstract: OBJECTIVE
  The immune effects of EGFR tyrosine kinase inhibitors (EGFR-TKIs) are poorly understood. Identifying immune biomarkers could guide patient selection and optimisation of EGFR-TKI-immunotherapy combinations.
  
  
  METHODS
  33 patients with NSCLC treated with an EGFR-TKI were prospectively enrolled. Peripheral blood mononuclear cells were collected pre-treatment, and after 1, 3 and 8 weeks. Flow cytometry was used to identify immune cell subsets, including PD-1 and PD-L1 expressing T cells. Immune parameters were correlated with clinical outcomes.
  
  
  RESULTS
  Compared to healthy donors (n=10), patients had higher pre-treatment proportions of proliferating and PD-L1(+)CD3(+) T cells (p<0.001). Compared to patients with an EGFR mutation (n=12), patients without a known mutation (n=21) had higher proportions of proliferating CD4(+) and PD-L1(+)CD3(+) T cells (p=0.03). There was a significant increase in PD-L1(+) T cells after 1 week of EGFR-TKI in patients whose disease progressed compared to non-progressors. Patients with higher PD-L1(+)CD3(+) T cells at 1-week were more likely to progress (OR 30.3, p<0.01) and had shorter PFS (1.6 vs. 8.8m; p<0.01) and OS (3.8 vs 23.2m; p<0.001) than those with fewer PD-L1(+)CD3(+) T cells. On multivariate analysis, high PD-L1(+)CD3(+) T cells was the only independent predictor for PFS (HR 3.7, p=0.01), while for OS independent predictors were high PD-L1(+)CD3(+) T cells (HR 6.5, p<0.01) and EGFR-negative status (HR 3.3, p=0.04).
  
  
  CONCLUSIONS
  There was a significant correlation between PD-L1 expression on peripheral T cells and clinical outcomes in EGFR-TKI-treated NSCLC. This warrants further validation as a blood-based biomarker that may identify candidates for PD-1 inhibitors or immunotherapy-EGFR-TKI combinations.
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia; Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia; National Centre for Asbestos Related Disease, University of Western Australia, Crawley, Western Australia, Australia. Electronic address: tarek.meniawy@uwa.edu.au.
authors.forename: Tarek M
authors.initials: TM
authors.lastname: Meniawy
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia; National Centre for Asbestos Related Disease, University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lake
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia; National Centre for Asbestos Related Disease, University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Alison M
authors.initials: AM
authors.lastname: McDonnell
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia; Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Millward
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia; Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia; National Centre for Asbestos Related Disease, University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Nowak
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D060890:B7-H1 Antigen / Q000378:metabolism*; D015415:Biomarkers; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality*; D016022:Case-Control Studies; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019233:Retreatment; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; D015415:Biomarkers; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors
keywords: Immune resistance; Lung cancer; Programmed death receptor-1; Protein tyrosine kinases; Tumor immunology