PMID- 28650338 OWN - NLM STAT- MEDLINE DCOM- 20171009 LR - 20220321 IS - 1558-8238 (Electronic) IS - 0021-9738 (Print) IS - 0021-9738 (Linking) VI - 127 IP - 8 DP - 2017 Aug 1 TI - IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade. PG - 2930-2940 LID - 91190 [pii] LID - 10.1172/JCI91190 [doi] AB - Programmed death-1-directed (PD-1-directed) immune checkpoint blockade results in durable antitumor activity in many advanced malignancies. Recent studies suggest that IFN-gamma 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-gamma-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. FAU - Ayers, Mark AU - Ayers M AD - Merck & Co. Inc., Kenilworth, New Jersey, USA. FAU - Lunceford, Jared AU - Lunceford J AD - Merck & Co. Inc., Kenilworth, New Jersey, USA. FAU - Nebozhyn, Michael AU - Nebozhyn M AD - Merck & Co. Inc., Kenilworth, New Jersey, USA. FAU - Murphy, Erin AU - Murphy E AD - Merck & Co. Inc., Kenilworth, New Jersey, USA. FAU - Loboda, Andrey AU - Loboda A AD - Merck & Co. Inc., Kenilworth, New Jersey, USA. FAU - Kaufman, David R AU - Kaufman DR AD - Merck & Co. Inc., Kenilworth, New Jersey, USA. FAU - Albright, Andrew AU - Albright A AD - Merck & Co. Inc., Kenilworth, New Jersey, USA. FAU - Cheng, Jonathan D AU - Cheng JD AD - Merck & Co. Inc., Kenilworth, New Jersey, USA. FAU - Kang, S Peter AU - Kang SP AD - Merck & Co. Inc., Kenilworth, New Jersey, USA. FAU - Shankaran, Veena AU - Shankaran V AD - University of Washington, Seattle, Washington, USA. FAU - Piha-Paul, Sarina A AU - Piha-Paul SA AD - University of Texas MD Anderson Cancer Center, Houston, Texas, USA. FAU - Yearley, Jennifer AU - Yearley J AD - Merck & Co. Inc., Kenilworth, New Jersey, USA. FAU - Seiwert, Tanguy Y AU - Seiwert TY AD - University of Chicago, Chicago, Illinois, USA. FAU - Ribas, Antoni AU - Ribas A AD - UCLA, Los Angeles, California, USA. FAU - McClanahan, Terrill K AU - McClanahan TK AD - Merck & Co. Inc., Kenilworth, New Jersey, USA. LA - eng PT - Clinical Trial, Phase I PT - Journal Article PT - Randomized Controlled Trial DEP - 20170626 PL - United States TA - J Clin Invest JT - The Journal of clinical investigation JID - 7802877 RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents) RN - 0 (B7-H1 Antigen) RN - 0 (CD274 protein, human) RN - 0 (IFNG protein, human) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) RN - 82115-62-6 (Interferon-gamma) RN - DPT0O3T46P (pembrolizumab) SB - IM MH - Antibodies, Monoclonal, Humanized/*therapeutic use MH - Antineoplastic Agents/*therapeutic use MH - B7-H1 Antigen/metabolism MH - Biopsy MH - Carcinoma/drug therapy/immunology MH - Carcinoma, Non-Small-Cell Lung/drug therapy/immunology MH - *Gene Expression Profiling MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Immune System MH - Immunohistochemistry MH - Interferon-gamma/*metabolism MH - Lung Neoplasms/drug therapy/immunology MH - Melanoma/drug therapy/immunology MH - Pilot Projects MH - Programmed Cell Death 1 Receptor/*antagonists & inhibitors/metabolism MH - ROC Curve MH - Sequence Analysis, RNA MH - Signal Transduction MH - Skin Neoplasms/drug therapy/immunology MH - Stomach Neoplasms/drug therapy/*immunology MH - Treatment Outcome MH - Tumor Microenvironment PMC - PMC5531419 COIS- Conflict of interest: M. Ayers, J. Lunceford, M. Nebozhyn, E. Murphy, A. Loboda, D.R. Kaufman, A. Albright, J.D. Cheng, S.P. Kang, J. Yearley, and T.K. McClanahan are employees of Merck & Co. Inc. S.P. Kang and T.K. McClanahan also disclose stock ownership in Merck & Co. Inc. M. Ayers, J. Lunceford, E. Murphy, A. Loboda, and T.K. McClanahan have a patent pending (system and methods for deriving gene signature biomarkers of response to PD-1 antagonists; PCT/US2015/064445), and S.P. Kang has a patent pending (MK-3475). V. Shankaran received a grant from Merck & Co. Inc. during the conduct of the study and has received grants from Amgen and Castle Biosciences. T.Y. Seiwert reports personal fees from Merck & Co. Inc. during the conduct of the study. A. Ribas has been a consultant for Merck & Co. Inc., with the honoraria paid to his institution. EDAT- 2017/06/27 06:00 MHDA- 2017/10/11 06:00 PMCR- 2017/11/01 CRDT- 2017/06/27 06:00 PHST- 2016/10/12 00:00 [received] PHST- 2017/05/11 00:00 [accepted] PHST- 2017/06/27 06:00 [pubmed] PHST- 2017/10/11 06:00 [medline] PHST- 2017/06/27 06:00 [entrez] PHST- 2017/11/01 00:00 [pmc-release] AID - 91190 [pii] AID - 10.1172/JCI91190 [doi] PST - ppublish SO - J Clin Invest. 2017 Aug 1;127(8):2930-2940. doi: 10.1172/JCI91190. Epub 2017 Jun 26.