Antonio Calles1, Xiaoyun Liao, Lynette M Sholl, Scott J Rodig, Gordon J Freeman, Mohit Butaney, Christine Lydon, Suzanne E Dahlberg, F Stephen Hodi, Geoffrey R Oxnard, David M Jackman, Pasi A Jänne. 1. *Department of Medical Oncology, †Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; ‡Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; §Harvard Medical School, Boston, Massachusetts; ‖Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts. ¶Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; and #Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
Abstract
INTRODUCTION: Clinical responses to immune checkpoint blockade by anti-programmed cell death protein-1 (PD-1)/PD-L1 monoclonal antibodies in non-small-cell lung cancer (NSCLC) are associated with PD-L1 expression and smoking status. We aimed to determine the expression profile of PD-1 and its ligands, PD-L1 and PD-L2, in both smokers and never smokers patients with KRAS-mutant NSCLC. METHODS: We retrospectively analyzed the clinical and molecular characteristics of 114 KRAS-mutant NSCLC patients (84 smokers and 30 never smokers) and their clinical tumor samples for the expression of PD-1, PD-L1, and PD-L2 by immunohistochemistry (IHC). We used murine monoclonal antibodies anti-PD-L1 (clone 9A11) and anti-PD-L2 (clone 9E5) to examine for tumor cell expression (0, negative; 1, weak; 2, moderate; 3, intense) and anti-PD-1 (clone EH33) for tumor-infiltrating lymphocytes. RESULTS: PD-L1 expression was detected in 27 of 114 patients (24%; 95% confidence interval [CI], 16-33%) and associated with smoking status (current smokers, 44%; former smokers, 20%; never smokers, 13%; p = 0.03). Higher intensity of PD-L1 expression (IHC-2+/IHC-3+) was more frequently observed in smokers and associated with more pack-years. PD-L2 was positive in 54 of 114 patients (47%; 95% CI, 38-57%) and not related to smoking status. PD-1-positive tumor-infiltrating lymphocytes were present in 77 of 114 tumor specimens tested (68%; 95% CI, 59-77%) including 21 of 27 samples with PD-L1 expression and 39 of 54 samples with PD-L2-positive expression. We found that PD-L1 expression fades with the age of the specimens used for analyses decreasing beyond 3 years (p = 0.016). CONCLUSIONS: The expression of PD-1 and its ligands PD-L1 and PD-L2 is heterogeneous within KRAS-mutant NSCLC and suggests an inducible expression of PD-L1 by smoking.
INTRODUCTION: Clinical responses to immune checkpoint blockade by anti-programmed cell death protein-1 (PD-1)/PD-L1 monoclonal antibodies in non-small-cell lung cancer (NSCLC) are associated with PD-L1 expression and smoking status. We aimed to determine the expression profile of PD-1 and its ligands, PD-L1 and PD-L2, in both smokers and never smokers patients with KRAS-mutant NSCLC. METHODS: We retrospectively analyzed the clinical and molecular characteristics of 114 KRAS-mutant NSCLCpatients (84 smokers and 30 never smokers) and their clinical tumor samples for the expression of PD-1, PD-L1, and PD-L2 by immunohistochemistry (IHC). We used murine monoclonal antibodies anti-PD-L1 (clone 9A11) and anti-PD-L2 (clone 9E5) to examine for tumor cell expression (0, negative; 1, weak; 2, moderate; 3, intense) and anti-PD-1 (clone EH33) for tumor-infiltrating lymphocytes. RESULTS:PD-L1 expression was detected in 27 of 114 patients (24%; 95% confidence interval [CI], 16-33%) and associated with smoking status (current smokers, 44%; former smokers, 20%; never smokers, 13%; p = 0.03). Higher intensity of PD-L1 expression (IHC-2+/IHC-3+) was more frequently observed in smokers and associated with more pack-years. PD-L2 was positive in 54 of 114 patients (47%; 95% CI, 38-57%) and not related to smoking status. PD-1-positive tumor-infiltrating lymphocytes were present in 77 of 114 tumor specimens tested (68%; 95% CI, 59-77%) including 21 of 27 samples with PD-L1 expression and 39 of 54 samples with PD-L2-positive expression. We found that PD-L1 expression fades with the age of the specimens used for analyses decreasing beyond 3 years (p = 0.016). CONCLUSIONS: The expression of PD-1 and its ligands PD-L1 and PD-L2 is heterogeneous within KRAS-mutant NSCLC and suggests an inducible expression of PD-L1 by smoking.
Authors: Annacarolina da Silva; Michaela Bowden; Sui Zhang; Yohei Masugi; Aaron R Thorner; Zachary T Herbert; Chensheng Willa Zhou; Lauren Brais; Jennifer A Chan; F Stephen Hodi; Scott Rodig; Shuji Ogino; Matthew H Kulke Journal: Pancreas Date: 2018-10 Impact factor: 3.327
Authors: Austin K Mattox; Jina Lee; William H Westra; Robert H Pierce; Ronald Ghossein; William C Faquin; Thomas J Diefenbach; Luc G Morris; Derrick T Lin; Lori J Wirth; Armida Lefranc-Torres; Eiichi Ishida; Patrick D Chakravarty; Lauren Johnson; Yang C Zeng; Huabiao Chen; Mark C Poznansky; Neil M Iyengar; Sara I Pai Journal: Cancer Res Date: 2017-09-25 Impact factor: 12.701
Authors: Patrick H Lizotte; Elena V Ivanova; Mark M Awad; Robert E Jones; Lauren Keogh; Hongye Liu; Ruben Dries; Christina Almonte; Grit S Herter-Sprie; Abigail Santos; Nora B Feeney; Cloud P Paweletz; Meghana M Kulkarni; Adam J Bass; Anil K Rustgi; Guo-Cheng Yuan; Donald W Kufe; Pasi A Jänne; Peter S Hammerman; Lynette M Sholl; F Stephen Hodi; William G Richards; Raphael Bueno; Jessie M English; Mark A Bittinger; Kwok-Kin Wong Journal: JCI Insight Date: 2016-09-08