Purpose: To determine the tumor tissue/cell distribution, functional associations and clinical significance of PD-1, LAG-3 and TIM-3 in human non-small-cell lung cancer (NSCLC). Experimental Design: Using multiplexed quantitative immunofluorescence (QIF) we measured CD3, PD-1, LAG-3 and TIM-3 in >800 NSCLCs from three tissuemicroarray-based cohorts. Associations between markers and tumor genomics were studied in TCGA-NSCLC dataset. Using mass-cytometry (CyTOF) analysis from 20 resected NSCLCs, we determined the levels, co-expression and functional profile of PD-1, LAG-3 and TIM-3 expressing immune cells. Finally, we measured the markers in 90 NSCLCs from patients treated with PD-1 axis blockers. Results: PD-1, LAG-3 and TIM-3 were detected in TILs from 55%, 41.5% and 25.3% of cases, respectively. These markers showed association with each other, but not with clinicopathologic variables and survival in cases without immunotherapy. The markers were lower in EGFR-mutated adenocarcinomas and partially associated with tumor-mutational burden. In single-cell CyTOF analysis, PD-1 and LAG-3 were predominantly localized on T/NKT-cells; while TIM-3 was higher in NK-cells and macrophages. Co-expression of PD-1,LAG-3 and TIM-3 was associated with T-cell activation, effector function and proliferation, but also with pro-apoptotic markers. LAG-3 and TIM-3 were present in TILs lacking PD-1 and elevated baseline LAG-3 was associated with shorter progression-free survival after PD-1 axis blockade. Conclusions: PD-1, LAG-3 and TIM-3 have distinct tissue/cell distribution, functional implications and genomic correlates in NSCLC. Expression of these receptors is associated with activation, but also with pro-apoptotic T-cell phenotype. Elevated LAG-3 is associated with insensitivity to PD-1 blockade suggesting independence of these immune evasion pathways.
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