Title | IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR, Albright A, Cheng JD, S Kang P, Shankaran V, Piha-Paul SA, Yearley J, Seiwert TY, Ribas A, McClanahan TK |
Journal | J Clin Invest |
Volume | 127 |
Issue | 8 |
Pagination | 2930-2940 |
Date Published | 2017 Aug 01 |
ISSN | 1558-8238 |
Keywords | Antibodies, Monoclonal, Humanized, Antineoplastic Agents, B7-H1 Antigen, Biopsy, Carcinoma, Carcinoma, Non-Small-Cell Lung, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Immune System, Immunohistochemistry, Interferon-gamma, Lung Neoplasms, Melanoma, Pilot Projects, Programmed Cell Death 1 Receptor, ROC Curve, Sequence Analysis, RNA, Signal Transduction, Skin Neoplasms, Stomach Neoplasms, Treatment Outcome, Tumor Microenvironment |
Abstract | Programmed death-1-directed (PD-1-directed) immune checkpoint blockade results in durable antitumor activity in many advanced malignancies. Recent studies suggest that IFN-γ is a critical driver of programmed death ligand-1 (PD-L1) expression in cancer and host cells, and baseline intratumoral T cell infiltration may improve response likelihood to anti-PD-1 therapies, including pembrolizumab. However, whether quantifying T cell-inflamed microenvironment is a useful pan-tumor determinant of PD-1-directed therapy response has not been rigorously evaluated. Here, we analyzed gene expression profiles (GEPs) using RNA from baseline tumor samples of pembrolizumab-treated patients. We identified immune-related signatures correlating with clinical benefit using a learn-and-confirm paradigm based on data from different clinical studies of pembrolizumab, starting with a small pilot of 19 melanoma patients and eventually defining a pan-tumor T cell-inflamed GEP in 220 patients with 9 cancers. Predictive value was independently confirmed and compared with that of PD-L1 immunohistochemistry in 96 patients with head and neck squamous cell carcinoma. The T cell-inflamed GEP contained IFN-γ-responsive genes related to antigen presentation, chemokine expression, cytotoxic activity, and adaptive immune resistance, and these features were necessary, but not always sufficient, for clinical benefit. The T cell-inflamed GEP has been developed into a clinical-grade assay that is currently being evaluated in ongoing pembrolizumab trials. |
DOI | 10.1172/JCI91190 |
Alternate Journal | J. Clin. Invest. |
PubMed ID | 28650338 |
PubMed Central ID | PMC5531419 |
Submitted by kej2006 on June 6, 2018 - 4:12pm