%0 Journal Article
%A Pabla, Sarabjot
%A Conroy, Jeffrey M
%A Nesline, Mary K
%A Glenn, Sean T
%A Papanicolau-Sengos, Antonios
%A Burgher, Blake
%A Hagen, Jacob
%A Giamo, Vincent
%A Andreas, Jonathan
%A Lenzo, Felicia L
%A Yirong, Wang
%A Dy, Grace K
%A Yau, Edwin
%A Early, Amy
%A Chen, Hongbin
%A Bshara, Wiam
%A Madden, Katherine G
%A Shirai, Keisuke
%A Dragnev, Konstantin
%A Tafe, Laura J
%A Marin, Daniele
%A Zhu, Jason
%A Clarke, Jeff
%A Labriola, Matthew
%A McCall, Shannon
%A Zhang, Tian
%A Zibelman, Matthew
%A Ghatalia, Pooja
%A Araujo-Fernandez, Isabel
%A Singavi, Arun
%A George, Ben
%A MacKinnon, Andrew Craig
%A Thompson, Jonathan
%A Singh, Rajbir
%A Jacob, Robin
%A Dressler, Lynn
%A Steciuk, Mark
%A Binns, Oliver
%A Kasuganti, Deepa
%A Shah, Neel
%A Ernstoff, Marc
%A Odunsi, Kunle
%A Kurzrock, Razelle
%A Gardner, Mark
%A Galluzzi, Lorenzo
%A Morrison, Carl
%T Proliferative potential and resistance to immune checkpoint blockade in lung cancer patients.
%D 2019
%U http://hdl.handle.net/10668/13497
%X Resistance to immune checkpoint inhibitors (ICIs) has been linked to local immunosuppression independent of major ICI targets (e.g., PD-1). Clinical experience with response prediction based on PD-L1 expression suggests that other factors influence sensitivity to ICIs in non-small cell lung cancer (NSCLC) patients. Tumor specimens from 120 NSCLC patients from 10 institutions were evaluated for PD-L1 expression by immunohistochemistry, and global proliferative profile by targeted RNA-seq. Cell proliferation, derived from the mean expression of 10 proliferation-associated genes (namely BUB1, CCNB2, CDK1, CDKN3, FOXM1, KIAA0101, MAD2L1, MELK, MKI67, and TOP2A), was identified as a marker of response to ICIs in NSCLC. Poorly, moderately, and highly proliferative tumors were somewhat equally represented in NSCLC, with tumors with the highest PD-L1 expression being more frequently moderately proliferative as compared to lesser levels of PD-L1 expression. Proliferation status had an impact on survival in patients with both PD-L1 positive and negative tumors. There was a significant survival advantage for moderately proliferative tumors compared to their combined highly/poorly counterparts (p = 0.021). Moderately proliferative PD-L1 positive tumors had a median survival of 14.6 months that was almost twice that of PD-L1 negative highly/poorly proliferative at 7.6 months (p = 0.028). Median survival in moderately proliferative PD-L1 negative tumors at 12.6 months was comparable to that of highly/poorly proliferative PD-L1 positive tumors at 11.5 months, but in both instances less than that of moderately proliferative PD-L1 positive tumors. Similar to survival, proliferation status has impact on disease control (DC) in patients with both PD-L1 positive and negative tumors. Patients with moderately versus those with poorly or highly proliferative tumors have a superior DC rate when combined with any classification schema used to score PD-L1 as a positive result (i.e., TPS ≥ 50% or ≥ 1%), and best displayed by a DC rate for moderately proliferative tumors of no less than 40% for any classification of PD-L1 as a negative result. While there is an over representation of moderately proliferative tumors as PD-L1 expression increases this does not account for the improved survival or higher disease control rates seen in PD-L1 negative tumors. Cell proliferation is potentially a new biomarker of response to ICIs in NSCLC and is applicable to PD-L1 negative tumors.
%K Atezolizumab
%K Ipilimumab
%K Nivolumab
%K PD-1
%K Pembrolizumab
%~