Proliferative potential and resistance to immune checkpoint blockade in lung cancer patients. Issue 1 (1st February 2019)

• Record Type: Journal Article
• Authors: Pabla, Sarabjot; Conroy, Jeffrey M.; Nesline, Mary K.; Glenn, Sean T.; Papanicolau-Sengos, Antonios; Burgher, Blake; Hagen, Jacob; Giamo, Vincent; Andreas, Jonathan; Lenzo, Felicia L.; Yirong, Wang; Dy, Grace K.; Yau, Edwin; Early, Amy; Chen, Hongbin; Bshara, Wiam; Madden, Katherine G.; Shirai, Keisuke; Dragnev, Konstantin; Tafe, Laura J.; Marin, Daniele; Zhu, Jason; Clarke, Jeff; Labriola, Matthew; McCall, Shannon; Zhang, Tian; Zibelman, Matthew; Ghatalia, Pooja; Araujo-Fernandez, Isabel; Singavi, Arun; George, Ben; MacKinnon, Andrew Craig; Thompson, Jonathan; Singh, Rajbir; Jacob, Robin; Dressler, Lynn; Steciuk, Mark; Binns, Oliver; Kasuganti, Deepa; Shah, Neel; Ernstoff, Marc; Odunsi, Kunle; Kurzrock, Razelle; Gardner, Mark; Galluzzi, Lorenzo; Morrison, Carl;
• Is Part Of: Journal for immunotherapy of cancer. Volume 7:Issue 1(2019)
• Publication Date: 2019-02-01
• Subjects: Atezolizumab -- Nivolumab -- Pembrolizumab -- Ipilimumab -- PD-1; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1186/s40425-019-0506-3
• Languages: English
• ISSNs: 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.