Tarek M Meniawy1, Richard A Lake2, Alison M McDonnell2, Michael J Millward3, Anna K Nowak4. 1. 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. 2. 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. 3. 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. 4. 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.
Abstract
OBJECTIVES: 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. MATERIALS AND 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.
OBJECTIVES: 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. MATERIALS AND 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.
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