Stk11/Lkb1 ablation directly promotes primary resistance to PD-L1/PD-1 blockade in immunocompetent murine models of Kras-mutant LUAC. Stk11/Lkb1-proficient/deficient.

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Stk11/Lkb1 ablation directly promotes primary resistance to PD-L1/PD-1 blockade in immunocompetent murine models of Kras-mutant LUAC. Stk11/Lkb1-proficient/deficient isogenic derivatives of the LKR13 (A) and LKR10 (B) cell lines were used in preclinical exp... Stk11/Lkb1 ablation directly promotes primary resistance to PD-L1/PD-1 blockade in immunocompetent murine models of Kras-mutant LUAC. Stk11/Lkb1-proficient/deficient isogenic derivatives of the LKR13 (A) and LKR10 (B) cell lines were used in preclinical experiments. Changes in mean (main panels) and individual (inset panels) subcutaneous tumor volume following treatment with (A) anti–PD-L1 (mIgG1-D265AFc clone 80) or IgG control antibody (LKR13/LKR13KO isogenic pair) and (B) anti–PD-1 mAb (clone RMPI-14; BioXCell) or isotype control antibody (clone 2A3; BioXCell; LKR10/LKR10KO isogenic pair) are graphed. Error bars represent SEM. Mean tumor volume plots are depicted from the time of randomization to the time that the first mouse in any of the two treatment arms was sacrificed. Spider plots indicate individual tumor volume trajectories for the entire duration of the in vivo experiment (25 days for the LKR13/LKR13KO and 39 days for the LKR10/LKR10KO model). Note that PD-1/PD-L1 blockade blunts the in vivo growth of Stk11/Lkb1-proficient Kras-mutant LUAC, whereas Stk11/Lkb1 knockout renders tumors recalcitrant to PD-1/PD-L1 inhibition. The Mann–Whitney U test was used to compare mean tumor volumes between IgG control and anti–PD-L1/anti–PD-1–treated mice in each syngeneic model. Asterisks denote statistical significance at the P ≤ 0.05 (*) and P ≤ 0.01 (**) level. Ferdinandos Skoulidis et al. Cancer Discov 2018;8:822-835 ©2018 by American Association for Cancer Research