MP88-11 IMMUNE CORRELATES OF PATHOLOGIC RESPONSE IN BLADDER CANCER PATIENTS UNDERGOING NEOADJUVANT CHEMOTHERAPY

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology IV1 Apr 2017MP88-11 IMMUNE CORRELATES OF PATHOLOGIC RESPONSE IN BLADDER CANCER PATIENTS UNDERGOING NEOADJUVANT CHEMOTHERAPY Philip Abbosh, David Liu, Woonyoung Choid, Wafik El-Deiry, Jonathan Rosenberg, David McConkey, Elizabeth Plimack, and Eliezer Van Allen Philip AbboshPhilip Abbosh More articles by this author , David LiuDavid Liu More articles by this author , Woonyoung ChoidWoonyoung Choid More articles by this author , Wafik El-DeiryWafik El-Deiry More articles by this author , Jonathan RosenbergJonathan Rosenberg More articles by this author , David McConkeyDavid McConkey More articles by this author , Elizabeth PlimackElizabeth Plimack More articles by this author , and Eliezer Van AllenEliezer Van Allen More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2736AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The immune system is increasingly recognized as both a key player in cancer control and as druggable target. We hypothesized that the immune system impacts pathologic response in patients undergoing cisplatin-based neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer though the immune system. METHODS Whole exome sequencing (WES) was performed on tumor DNA from patients in two independent cohorts who underwent cisplatin-based NAC. The Memorial Sloan Kettering / Dana Farber Cancer Institute (n=50; 25 responders) and Philadelphia (n=48; 20 responders) cohorts were treated with gemcitabine / cisplatin or methotrexate / vinblastine / doxorubicin / cisplatin. Mutation analysis was performed using standard analytical pipelines. Macrohistocompatibility complex (MHC)-restricted neoantigens were identified with netMHCpan and PolySolver. High affinity neoantigens were defined to have ≤500 nM binding affinity (Kd). Pathologic response was defined as ≤ypTis cystectomy specimen. CIBERSORT was used to infer immune cell infiltrate based on DASL Illumina microarray expression profiles (n=41; 17 responders). RESULTS Chemoresponders had >twice as many putative neoantigens as nonresponders (471 vs 207 neoantigens respectively; p=1x10-6, Wilcoxon). This relationship maintained significance when neoantigens were limited to Kd≤100 nM or ≤50 nM, and when chemoresponse was defined as ypT0-only, or ≤ypT1. ERCC2 loss-of-function mutations were 36% sensitive in identifying chemoresponders but 96% specific. Above-median neoantigen burden was 81% sensitive in identifying chemoresponders and 78% specific. CD8+ cells were enriched in responders (13.5% vs 8.4% of infiltrate; p<0.008, t-test) as were activated NK cells (15.5% vs 12.7%; p=0.05). In 28 samples where WES and CIBERSORT data was available, the neoantigen burden was correlated to the CD8+ infiltrate value (R2=0.33, Pearson). CONCLUSIONS Neoantigen burden and CD8+ infiltrate correlate strongly with chemoresponse. Neoantigen burden and CD8+ infiltrate are directly proportional. NAC may therefore exert known tumor cell autonomous effects and an extrinsic effect involving the immune system via neoantigens. Anti-neoantigen responses have been shown to impact immune checkpoint responses and a similar mechanism may mediate cytotoxic chemoresponse. Experiments are underway to directly and functionally characterize the effect of the immune system in chemoresponse. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1178 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Philip Abbosh More articles by this author David Liu More articles by this author Woonyoung Choid More articles by this author Wafik El-Deiry More articles by this author Jonathan Rosenberg More articles by this author David McConkey More articles by this author Elizabeth Plimack More articles by this author Eliezer Van Allen More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...