Proliferative potential and resistance to immune checkpoint blockade in lung cancer patients. J Immunother Cancer 2019 Feb 01;7(1):27
Date
02/03/2019Pubmed ID
30709424Pubmed Central ID
PMC6359802DOI
10.1186/s40425-019-0506-3Scopus ID
2-s2.0-85060929943 (requires institutional sign-in at Scopus site) 61 CitationsAbstract
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.
Author List
Pabla S, Conroy JM, Nesline MK, Glenn ST, Papanicolau-Sengos A, Burgher B, Hagen J, Giamo V, Andreas J, Lenzo FL, Yirong W, Dy GK, Yau E, Early A, Chen H, Bshara W, Madden KG, Shirai K, Dragnev K, Tafe LJ, Marin D, Zhu J, Clarke J, Labriola M, McCall S, Zhang T, Zibelman M, Ghatalia P, Araujo-Fernandez I, Singavi A, George B, MacKinnon AC, Thompson J, Singh R, Jacob R, Dressler L, Steciuk M, Binns O, Kasuganti D, Shah N, Ernstoff M, Odunsi K, Kurzrock R, Gardner M, Galluzzi L, Morrison CAuthors
Ben George MD Professor in the Medicine department at Medical College of WisconsinRazelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin
Jonathan R. Thompson MD Assistant Professor in the Medicine department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AdultAged
Aged, 80 and over
Antineoplastic Agents, Immunological
B7-H1 Antigen
Base Sequence
Biomarkers
Carcinoma, Non-Small-Cell Lung
Cell Proliferation
Drug Resistance, Neoplasm
Female
Humans
Lung Neoplasms
Male
Middle Aged
Survival Analysis
