Nuclear IRF-1 expression as a mechanism to assess "Capability" to express PD-L1 and response to PD-1 therapy in metastatic melanoma.
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.



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.



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).



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.
Department of Pathology, BML116 Yale School of Medicine, 310 Cedar Street, PO Box 208023, 06520 New Haven, CT USA.
James W
JW
Smithy
Department of Pathology, BML116 Yale School of Medicine, 310 Cedar Street, PO Box 208023, 06520 New Haven, CT USA.
Lauren M
LM
Moore
Department of Pathology, BML116 Yale School of Medicine, 310 Cedar Street, PO Box 208023, 06520 New Haven, CT USA.
Vasiliki
V
Pelekanou
Department of Pathology, BML116 Yale School of Medicine, 310 Cedar Street, PO Box 208023, 06520 New Haven, CT USA.
Jamaal
J
Rehman
Department of Pathology, BML116 Yale School of Medicine, 310 Cedar Street, PO Box 208023, 06520 New Haven, CT USA.
Patricia
P
Gaule
Department of Pathology, BML116 Yale School of Medicine, 310 Cedar Street, PO Box 208023, 06520 New Haven, CT USA.
Pok Fai
PF
Wong
Department of Pathology, BML116 Yale School of Medicine, 310 Cedar Street, PO Box 208023, 06520 New Haven, CT USA.
Veronique M
VM
Neumeister
Section of Medical Oncology, Yale School of Medicine, New Haven, CT USA.
Mario
M
Sznol
Section of Medical Oncology, Yale School of Medicine, New Haven, CT USA.
Harriet M
HM
Kluger
Department of Pathology, BML116 Yale School of Medicine, 310 Cedar Street, PO Box 208023, 06520 New Haven, CT USA.|Section of Medical Oncology, Yale School of Medicine, New Haven, CT USA.
David L
DL
Rimm
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D060890:B7-H1 Antigen / Q000235:genetics* / Q000276:immunology; D054316:Biomarkers, Pharmacological; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects; D050856:Interferon Regulatory Factor-1 / Q000235:genetics*; D000074324:Ipilimumab / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D016609:Neoplasms, Second Primary / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D060890:B7-H1 Antigen; D054316:Biomarkers, Pharmacological; C423236:CD274 protein, human; D050856:Interferon Regulatory Factor-1; D000074324:Ipilimumab; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab; C582435:pembrolizumab
Biomarkers; IRF-1; Melanoma; PD-L1