Immune-Active Microenvironment in Small Cell Carcinoma of the Ovary, Hypercalcemic Type: Rationale for Immune Checkpoint Blockade

被引:122
作者
Jelinic, Petar [1 ]
Ricca, Jacob [2 ,3 ]
Van Oudenhove, Elke [1 ]
Olvera, Narciso [1 ]
Merghoub, Taha [3 ]
Levine, Douglas A. [1 ]
Zamarin, Dmitriy [2 ,3 ]
机构
[1] NYU, Langone Med Ctr, Gynecol Oncol Laura & Isaac Perlmutter Canc Ctr, New York, NY USA
[2] Mem Sloan Kettering Canc Ctr, Gynecol Med Oncol Serv, Dept Med, 1275 York Ave, New York, NY 10065 USA
[3] Mem Sloan Kettering Canc Ctr, Gynecol Med Oncol Serv, Ludwig Collaborat Lab, 1275 York Ave, New York, NY 10021 USA
来源
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE | 2018年 / 110卷 / 07期
关键词
TUMOR-INFILTRATING LYMPHOCYTES; INSTABLE ENDOMETRIAL CANCERS; PD-1; BLOCKADE; SMARCA4; MUTATIONS; NEOANTIGEN LOAD; LUNG-CANCER; EXPRESSION; ASSOCIATION; NIVOLUMAB; NUMBER;
D O I
10.1093/jnci/djx277
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a highly aggressive monogenic cancer driven by SMARCA4 mutations. Here, we report responses to anti-PD1 immunotherapy in four patients and characterize the immune landscape of SCCOHT tumors using quantitative immunofluorescence and gene expression profiling. Unexpectedly for a low mutation burden cancer, the majority of the tumors (eight of 11 cases) demonstrated PD-L1 expression with strong associated T-cell infiltration (R-2 = 0.60-0.95). PD-L1 expression was detected in both tumor and stromal cells, with macrophages being the most abundant PD-L1-positive cells in some tumors (three of 11 cases). Transcriptional profiling revealed increased expression of genes related to Th1 and cytotoxic cell function in PD-L1-high tumors, suggesting that PD-L1 acts as a pathway of adaptive immune resistance in SCCOHT. These findings suggest that although SCCOHT are low-mutational burden tumors, their immunogenic microenvironment resembles the landscape of tumors that respond well to treatment with PD-1/PD-L1 blockade.
引用
收藏
页码:787 / 790
页数:4
相关论文
共 23 条
[1]   IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade [J].
Ayers, Mark ;
Lunceford, Jared ;
Nebozhyn, Michael ;
Murphy, Erin ;
Loboda, Andrey ;
Kaufman, David R. ;
Albright, Andrew ;
Cheng, Jonathan D. ;
Kang, S. Peter ;
Shankaran, Veena ;
Piha-Paul, Sarina A. ;
Yearley, Jennifer ;
Seiwert, Tanguy Y. ;
Ribas, Antoni ;
McClanahan, Terrill K. .
JOURNAL OF CLINICAL INVESTIGATION, 2017, 127 (08) :2930-2940
[2]   Molecular and Biochemical Aspects of the PD-1 Checkpoint Pathway [J].
Boussiotis, Vassiliki A. .
NEW ENGLAND JOURNAL OF MEDICINE, 2016, 375 (18) :1767-1778
[3]   Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer [J].
Brahmer, Julie ;
Reckamp, Karen L. ;
Baas, Paul ;
Crino, Lucio ;
Eberhardt, Wilfried E. E. ;
Poddubskaya, Elena ;
Antonia, Scott ;
Pluzanski, Adam ;
Vokes, Everett E. ;
Holgado, Esther ;
Waterhouse, David ;
Ready, Neal ;
Gainor, Justin ;
Aren Frontera, Osvaldo ;
Havel, Libor ;
Steins, Martin ;
Garassino, Marina C. ;
Aerts, Joachim G. ;
Domine, Manuel ;
Paz-Ares, Luis ;
Reck, Martin ;
Baudelet, Christine ;
Harbison, Christopher T. ;
Lestini, Brian ;
Spigel, David R. .
NEW ENGLAND JOURNAL OF MEDICINE, 2015, 373 (02) :123-135
[4]   Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression [J].
Garcia-Diaz, Angel ;
Shin, Daniel Sanghoon ;
Moreno, Blanca Homet ;
Saco, Justin ;
Escuin-Ordinas, Helena ;
Rodriguez, Gabriel Abril ;
Zaretsky, Jesse M. ;
Sun, Lu ;
Hugo, Willy ;
Wang, Xiaoyan ;
Parisi, Giulia ;
Saus, Cristina Puig ;
Torrejon, Davis Y. ;
Graeber, Thomas G. ;
Comin-Anduix, Begonya ;
Hu-Lieskovan, Siwen ;
Damoiseaux, Robert ;
Lo, Roger S. ;
Ribas, Antoni .
CELL REPORTS, 2017, 19 (06) :1189-1201
[5]   Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer [J].
Hamanishi, Junzo ;
Mandai, Masaki ;
Iwasaki, Masashi ;
Okazaki, Taku ;
Tanaka, Yoshimasa ;
Yamaguchi, Ken ;
Higuchi, Toshihiro ;
Yagi, Haruhiko ;
Takakura, Kenji ;
Minato, Nagahiro ;
Honjo, Tasuku ;
Fujii, Shingo .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (09) :3360-3365
[6]   Association of Polymerase e-Mutated and Microsatellite-Instable Endometrial Cancers With Neoantigen Load, Number of Tumor-Infiltrating Lymphocytes, and Expression of PD-1 and PD-L1 [J].
Howitt, Brooke E. ;
Shukla, Sachet A. ;
Sholl, Lynette M. ;
Ritterhouse, Lauren L. ;
Watkins, Jaclyn C. ;
Rodig, Scott ;
Stover, Elizabeth ;
Strickland, Kyle C. ;
D'Andrea, Alan D. ;
Wu, Catherine J. ;
Matulonis, Ursula A. ;
Konstantinopoulos, Panagiotis A. .
JAMA ONCOLOGY, 2015, 1 (09) :1319-1323
[7]   Concomitant loss of SMARCA2 and SMARCA4 expression in small cell carcinoma of the ovary, hypercalcemic type [J].
Jelinic, Petar ;
Schlappe, Brooke A. ;
Conlon, Niamh ;
Tseng, Jill ;
Olvera, Narciso ;
Dao, Fanny ;
Mueller, Jennifer J. ;
Hussein, Yaser ;
Soslow, Robert A. ;
Levine, Douglas A. .
MODERN PATHOLOGY, 2016, 29 (01) :60-66
[8]   Recurrent SMARCA4 mutations in small cell carcinoma of the ovary [J].
Jelinic, Petar ;
Mueller, Jennifer J. ;
Olveral, Narciso ;
Dao, Fanny ;
Scott, Sasinya N. ;
Shah, Ronak ;
Gao, JianJiong ;
Schultz, Nikolaus ;
Gonen, Mithat ;
Soslow, Robert A. ;
Berger, Michael F. ;
Levine, Douglas A. .
NATURE GENETICS, 2014, 46 (05) :424-426
[9]   Dual loss of the SWI/SNF complex ATPases SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcaemic type [J].
Karnezis, Anthony N. ;
Wang, Yemin ;
Ramos, Pilar ;
Hendricks, William P. D. ;
Oliva, Esther ;
D'Angelo, Emanuela ;
Prat, Jaime ;
Nucci, Marisa R. ;
Nielsen, Torsten O. ;
Chow, Christine ;
Leung, Samuel ;
Kommoss, Friedrich ;
Kommoss, Stefan ;
Silva, Annacarolina ;
Ronnett, Brigitte M. ;
Rabban, Joseph T. ;
Bowtell, David D. ;
Weissman, Bernard E. ;
Trent, Jeffrey M. ;
Gilks, C. Blake ;
Huntsman, David G. .
JOURNAL OF PATHOLOGY, 2016, 238 (03) :389-400
[10]   PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma [J].
Nghiem, Paul T. ;
Bhatia, Shailender ;
Lipson, Evan J. ;
Kudchadkar, Ragini R. ;
Miller, Natalie J. ;
Annamalai, Lakshmanan ;
Berry, Sneha ;
Chartash, Elliot K. ;
Daud, Adil ;
Fling, Steven P. ;
Friedlander, Philip A. ;
Kluger, Harriet M. ;
Kohrt, Holbrook E. ;
Lundgren, Lisa ;
Margolin, Kim ;
Mitchell, Alan ;
Olencki, Thomas ;
Pardoll, Drew M. ;
Reddy, Sunil A. ;
Shantha, Erica M. ;
Sharfman, William H. ;
Sharon, Elad ;
Shemanski, Lynn R. ;
Shinohara, Michi M. ;
Sunshine, Joel C. ;
Taube, Janis M. ;
Thompson, John A. ;
Townson, Steven M. ;
Yearley, Jennifer H. ;
Topalian, Suzanne L. ;
Cheever, Martin A. .
NEW ENGLAND JOURNAL OF MEDICINE, 2016, 374 (26) :2542-2552