학술논문
Proliferative potential and resistance to immune checkpoint blockade in lung cancer patients
Document Type
article
Author
Sarabjot Pabla; Jeffrey M. Conroy; Mary K. Nesline; Sean T. Glenn; Antonios Papanicolau-Sengos; Blake Burgher; Jacob Hagen; Vincent Giamo; Jonathan Andreas; Felicia L. Lenzo; Wang Yirong; Grace K. Dy; Edwin Yau; Amy Early; Hongbin Chen; Wiam Bshara; Katherine G. Madden; Keisuke Shirai; Konstantin Dragnev; Laura J. Tafe; Daniele Marin; Jason Zhu; Jeff Clarke; Matthew Labriola; Shannon McCall; Tian Zhang; Matthew Zibelman; Pooja Ghatalia; Isabel Araujo-Fernandez; Arun Singavi; Ben George; Andrew Craig MacKinnon; Jonathan Thompson; Rajbir Singh; Robin Jacob; Lynn Dressler; Mark Steciuk; Oliver Binns; Deepa Kasuganti; Neel Shah; Marc Ernstoff; Kunle Odunsi; Razelle Kurzrock; Mark Gardner; Lorenzo Galluzzi; Carl Morrison
Source
Journal for ImmunoTherapy of Cancer, Vol 7, Iss 1, Pp 1-13 (2019)
Subject
Language
English
ISSN
2051-1426
Abstract
Abstract Background 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. Methods 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. Results 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. Conclusions Cell proliferation is potentially a new biomarker of response to ICIs in NSCLC and is applicable to PD-L1 negative tumors.