PT - JOURNAL ARTICLE AU - Smithy, James W. AU - Moore, Lauren M. AU - Pelekanou, Vasiliki AU - Rehman, Jamaal AU - Gaule, Patricia AU - Wong, Pok Fai AU - Neumeister, Veronique M. AU - Sznol, Mario AU - Kluger, Harriet M. AU - Rimm, David L. TI - Nuclear IRF-1 expression as a mechanism to assess “Capability” to express PD-L1 and response to PD-1 therapy in metastatic melanoma AID - 10.1186/s40425-017-0229-2 DP - 2017 Dec 01 TA - Journal for ImmunoTherapy of Cancer PG - 25 VI - 5 IP - 1 4099 - http://jitc.bmj.com/content/5/1/25.short 4100 - http://jitc.bmj.com/content/5/1/25.full SO - J Immunother Cancer2017 Dec 01; 5 AB - Background Predictive biomarkers for antibodies against programmed death 1 (PD-1) remain a major unmet need in metastatic melanoma. Specifically, response is seen in tumors that do not express programmed death ligand 1 (PD-L1), highlighting the need for a more sensitive biomarker. We hypothesize that capacity to express PD-L1, as assessed by an assay for a PD-L1 transcription factor, interferon regulatory factor 1 (IRF-1), may better distinguish patients likely to benefit from anti-PD-1 immunotherapy.Methods Samples from 47 melanoma patients that received nivolumab, pembrolizumab, or combination ipilimumab/nivolumab at Yale New Haven Hospital from May 2013 to March 2016 were collected. Expression of IRF-1 and PD-L1 in archival pre-treatment formalin-fixed, paraffin-embedded tumor samples were assessed by the AQUA method of quantitative immunofluorescence. Objective radiographic response (ORR) and progression-free survival (PFS) were assessed using modified RECIST v1.1 criteria.Results Nuclear IRF-1 expression was higher in patients with partial or complete response (PR/CR) than in patients with stable or progressive disease (SD/PD) (p = 0.044). There was an insignificant trend toward higher PD-L1 expression in patients with PR/CR (p = 0.085). PFS was higher in the IRF-1-high group than the IRF-1-low group (p = 0.017), while PD-L1 expression had no effect on PFS (p = 0.83). In a subset analysis, a strong association with PFS is seen in patients treated with combination ipilimumab and nivolumab (p = 0.0051).Conclusions As a measure of PD-L1 expression capability, IRF-1 expression may be a more valuable predictive biomarker for anti-PD-1 therapy than PD-L1 itself.Abbreviations:BSABovine serum albuminCRComplete responseCTLA-4cytotoxic T-lymphocyte associated protein 4DAPI4’,6 diamidino-2-phenylindoleEtOHEthanolFDAFood and drug administrationFFPEFormalin-fixed, paraffin-embeddedFOVField of viewIFNγInterferon gammaIHCImmunohistochemicalIRF-1Interferon regulatory factor-1ORRObjective radiographic responseOSOverall survivalPBSPhosphate-buffered salinePDProgressive diseasePD-1Programmed death 1PD-L1Programmed death-ligand 1PFAParaformaldehydePFSProgression-free survivalPRPartial responseRTRoom temperatureSDStable diseaseTBSTTris-buffered saline + tweenTMATissue microarray