Pabla, SarabjotConroy, Jeffrey MNesline, Mary KGlenn, Sean TPapanicolau-Sengos, AntoniosBurgher, BlakeHagen, JacobGiamo, VincentAndreas, JonathanLenzo, Felicia LYirong, WangDy, Grace KYau, EdwinEarly, AmyChen, HongbinBshara, WiamMadden, Katherine GShirai, KeisukeDragnev, KonstantinTafe, Laura JMarin, DanieleZhu, JasonClarke, JeffLabriola, MatthewMcCall, ShannonZhang, TianZibelman, MatthewGhatalia, PoojaAraujo-Fernandez, IsabelSingavi, ArunGeorge, BenMacKinnon, Andrew CraigThompson, JonathanSingh, RajbirJacob, RobinDressler, LynnSteciuk, MarkBinns, OliverKasuganti, DeepaShah, NeelErnstoff, MarcOdunsi, KunleKurzrock, RazelleGardner, MarkGalluzzi, LorenzoMorrison, Carl2023-01-252023-01-252019-02-01http://hdl.handle.net/10668/13497Resistance 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.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/AtezolizumabIpilimumabNivolumabPD-1PembrolizumabAdultAgedAged, 80 and overAntineoplastic Agents, ImmunologicalB7-H1 AntigenBase SequenceBiomarkersCarcinoma, Non-Small-Cell LungCell ProliferationDrug Resistance, NeoplasmFemaleHumansLung NeoplasmsMaleMiddle AgedSurvival Analysisresearch article30709424open access10.1186/s40425-019-0506-32051-1426PMC6359802https://jitc.bmj.com/content/jitc/7/1/27.full.pdfhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359802/pdf