RT Journal Article
T1 Proliferative potential and resistance to immune checkpoint blockade in lung cancer patients.
A1 Pabla, Sarabjot
A1 Conroy, Jeffrey M
A1 Nesline, Mary K
A1 Glenn, Sean T
A1 Papanicolau-Sengos, Antonios
A1 Burgher, Blake
A1 Hagen, Jacob
A1 Giamo, Vincent
A1 Andreas, Jonathan
A1 Lenzo, Felicia L
A1 Yirong, Wang
A1 Dy, Grace K
A1 Yau, Edwin
A1 Early, Amy
A1 Chen, Hongbin
A1 Bshara, Wiam
A1 Madden, Katherine G
A1 Shirai, Keisuke
A1 Dragnev, Konstantin
A1 Tafe, Laura J
A1 Marin, Daniele
A1 Zhu, Jason
A1 Clarke, Jeff
A1 Labriola, Matthew
A1 McCall, Shannon
A1 Zhang, Tian
A1 Zibelman, Matthew
A1 Ghatalia, Pooja
A1 Araujo-Fernandez, Isabel
A1 Singavi, Arun
A1 George, Ben
A1 MacKinnon, Andrew Craig
A1 Thompson, Jonathan
A1 Singh, Rajbir
A1 Jacob, Robin
A1 Dressler, Lynn
A1 Steciuk, Mark
A1 Binns, Oliver
A1 Kasuganti, Deepa
A1 Shah, Neel
A1 Ernstoff, Marc
A1 Odunsi, Kunle
A1 Kurzrock, Razelle
A1 Gardner, Mark
A1 Galluzzi, Lorenzo
A1 Morrison, Carl
K1 Atezolizumab
K1 Ipilimumab
K1 Nivolumab
K1 PD-1
K1 Pembrolizumab
AB 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.
YR 2019
FD 2019-02-01
LK http://hdl.handle.net/10668/13497
UL http://hdl.handle.net/10668/13497
LA en
DS RISalud
RD Apr 20, 2025