Spatial signatures identify immune escape via PD-1 as a defining feature of T-cell/histiocyte-rich large B-cell lymphoma

被引:34
作者
Griffin, Gabriel K. [1 ]
Weirather, Jason L. [2 ]
Roemer, Margaretha G. M. [3 ,4 ]
Lipschitz, Mikel [1 ]
Kelley, Alyssa [1 ]
Chen, Pei-Hsuan [3 ]
Gusenleitner, Daniel [3 ]
Jeter, Erin [3 ]
Pak, Christine [3 ]
Gjini, Evisa [1 ]
Chapuy, Bjoern [3 ,5 ]
Rosenthal, Michael H. [6 ]
Xu, Jie [7 ]
Chen, Benjamin J. [8 ]
Sohani, Aliyah R. [9 ]
Lovitch, Scott B. [1 ]
Abramson, Jeremy S. [10 ]
Ishizuka, Jeffrey J. [3 ,11 ]
Kim, Austin, I [3 ]
Jacobson, Caron A. [3 ]
LaCasce, Ann S. [3 ]
Fletcher, Christopher D. [1 ]
Neuberg, Donna [2 ]
Freeman, Gordon J. [3 ]
Hodi, F. Stephen [3 ]
Wright, Kyle [1 ]
Ligon, Azra H. [1 ]
Jacobsen, Eric D. [3 ]
Armand, Philippe [3 ]
Shipp, Margaret A. [3 ]
Rodig, Scott J. [1 ]
机构
[1] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA
[2] Dana Farber Canc Inst, Dept Data Sci, Boston, MA 02115 USA
[3] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
[4] Vrije Univ Amsterdam, Dept Pathol, Med Ctr, Amsterdam, Netherlands
[5] Univ Med Ctr, Dept Hematol & Oncol, Gottingen, Germany
[6] Dana Farber Canc Inst, Dept Imaging, Boston, MA 02115 USA
[7] Univ Texas MD Anderson Canc Ctr, Dept Hematopathol, Houston, TX 77030 USA
[8] UMass Mem Med Ctr, Dept Pathol, Worcester, MA USA
[9] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA
[10] Massachusetts Gen Hosp, Ctr Lymphoma, Boston, MA 02114 USA
[11] Yale Canc Ctr, Dept Med Oncol, New Haven, CT USA
基金
美国国家卫生研究院;
关键词
D O I
10.1182/blood.2020006464
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
T-cell/histiocyte-rich large B-cell lymphoma (TCRLBCL) is an aggressive variant of diffuse large B-cell lymphoma (DLBCL) characterized by rare malignant B cells within a robust but ineffective immune cell infiltrate. The mechanistic basis of immune escape in TCRLBCL is poorly defined and not targeted therapeutically. We performed a genetic and quantitative spatial analysis of the PD-1/PD-L1 pathway in a multi-institutional cohort of TCRLBCLs and found that malignant B cells harbored PD-L1/PD-L2 copy gain or amplification in 64% of cases, which was associated with increased PD-L1 expression (P = .0111). By directed and unsupervised spatial analyses of multiparametric cell phenotypic data within the tumor microenvironment, we found that TCRLBCL is characterized by tumor-immune "neighborhoods" in which malignant B cells are surrounded by exceptionally high numbers of PD-L1-expressing TAMs and PD-1(+) T cells. Furthermore, unbiased clustering of spatially resolved immune signatures distinguished TCRLBCL from related subtypes of B-cell lymphoma, including classic Hodgkin lymphoma (cHL) and DLBCL-NOS. Finally, we observed clinical responses to PD-1 blockade in 3 of 5 patients with relapsed/refractory TCRLBCL who were enrolled in clinical trials for refractory hematologic malignancies (NCT03316573; NCT01953692), including 2 complete responses and 1 partial response. Taken together, these data implicate PD-1 signaling as an immune escape pathway in TCRLBCL and also support the potential utility of spatially resolved immune signatures to aid the diagnostic classification and immunotherapeutic prioritization of diverse tumor types.
引用
收藏
页码:1353 / 1364
页数:12
相关论文
共 41 条
  • [1] Nivolumab for Relapsed/Refractory Diffuse Large B-Cell Lymphoma in Patients Ineligible for or Having Failed Autologous Transplantation: A Single-Arm, Phase II Study
    Ansell, Stephen M.
    Minnema, Monique C.
    Johnson, Peter
    Timmerman, John M.
    Armand, Philippe
    Shipp, Margaret A.
    Rodig, Scott J.
    Ligon, Azra H.
    Roemer, Margaretha G. M.
    Reddy, Nishitha
    Cohen, Jonathon B.
    Assouline, Sarit
    Poon, Michelle
    Sharma, Manish
    Kato, Kazunobu
    Samakoglu, Selda
    Sumbul, Anne
    Grigg, Andrew
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 2019, 37 (06) : 481 - +
  • [2] PD-1 Blockade with Nivolumab in Relapsed or Refractory Hodgkin's Lymphoma
    Ansell, Stephen M.
    Lesokhin, Alexander M.
    Borrello, Ivan
    Halwani, Ahmad
    Scott, Emma C.
    Gutierrez, Martin
    Schuster, Stephen J.
    Millenson, Michael M.
    Cattry, Deepika
    Freeman, Gordon J.
    Rodig, Scott J.
    Chapuy, Bjoern
    Ligon, Azra H.
    Zhu, Lili
    Grosso, Joseph F.
    Kim, Su Young
    Timmerman, John M.
    Shipp, Margaret A.
    Armand, Philippe
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 2015, 372 (04) : 311 - 319
  • [3] Single-Cell Transcriptome Analysis Reveals Disease-Defining T-cell Subsets in the Tumor Microenvironment of Classic Hodgkin Lymphoma
    Aoki, Tomohiro
    Chong, Lauren C.
    Takata, Katsuyoshi
    Milne, Katy
    Hav, Monirath
    Colombo, Anthony
    Chavez, Elizabeth A.
    Nissen, Michael
    Wang, Xuehai
    Miyata-Takata, Tomoko
    Lam, Vivian
    Vigano, Elena
    Woolcock, Bruce W.
    Telenius, Adele
    Li, Michael Y.
    Healy, Shannon
    Ghesquiere, Chanel
    Kos, Daniel
    Goodyear, Talia
    Veldman, Johanna
    Zhang, Allen W.
    Kim, Jubin
    Saberi, Saeed
    Ding, Jiarui
    Farinha, Pedro
    Weng, Andrew P.
    Savage, Kerry J.
    Scott, David W.
    Krystal, Gerald
    Nelson, Brad H.
    Mottok, Anja
    Merchant, Akil
    Shah, Sohrab P.
    Steidl, Christian
    [J]. CANCER DISCOVERY, 2020, 10 (03) : 406 - 421
  • [4] Pembrolizumab in Relapsed or Refractory Primary Mediastinal Large B-Cell Lymphoma
    Armand, Philippe
    Rodig, Scott
    Melnichenko, Vladimir
    Thieblemont, Catherine
    Bouabdallah, Kamal
    Tumyan, Gayane
    Ozcan, Muhit
    Portino, Sergio
    Fogliatto, Laura
    Caballero, Maria D.
    Walewski, Jan
    Gulbas, Zafer
    Ribrag, Vincent
    Christian, Beth
    Perini, Guilherme Fleury
    Salles, Gilles
    Svoboda, Jakub
    Zain, Jasmine
    Patel, Sanjay
    Chen, Pei-Hsuan
    Ligon, Azra H.
    Ouyang, Jing
    Neuberg, Donna
    Redd, Robert
    Chatterjee, Arkendu
    Balakumaran, Arun
    Orlowski, Robert
    Shipp, Margaret
    Zinzani, Pier Luigi
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 2019, 37 (34) : 3291 - +
  • [5] Nivolumab for Relapsed/Refractory Classic Hodgkin Lymphoma After Failure of Autologous Hematopoietic Cell Transplantation: Extended Follow-Up of the Multicohort Single-Arm Phase II CheckMate 205 Trial
    Armand, Philippe
    Engert, Andreas
    Younes, Anas
    Fanale, Michelle
    Santoro, Armando
    Zinzani, Pier Luigi
    Timmerman, John M.
    Collins, Graham P.
    Ramchandren, Radhakrishnan
    Cohen, Jonathon B.
    De Boer, Jan Paul
    Kuruvilla, John
    Savage, Kerry J.
    Trneny, Marek
    Shipp, Margaret A.
    Kato, Kazunobu
    Sumbul, Anne
    Farsaci, Benedetto
    Ansell, Stephen M.
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 2018, 36 (14) : 1428 - +
  • [6] Programmed Death-1 Blockade With Pembrolizumab in Patients With Classical Hodgkin Lymphoma After Brentuximab Vedotin Failure
    Armand, Philippe
    Shipp, Margaret A.
    Ribrag, Vincent
    Michot, Jean-Marie
    Zinzani, Pier Luigi
    Kuruvilla, John
    Snyder, Ellen S.
    Ricart, Alejandro D.
    Balakumaran, Arun
    Rose, Shelonitda
    Moskowitz, Craig H.
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 2016, 34 (31) : 3733 - +
  • [7] Modern management of relapsed and refractory aggressive B-cell lymphoma: A perspective on the current treatment landscape and patient selection for CAR T-cell therapy
    Bachanova, Veronika
    Perales, Miguel-Angel
    Abramson, Jeremy S.
    [J]. BLOOD REVIEWS, 2020, 40
  • [8] Dimensionality reduction for visualizing single-cell data using UMAP
    Becht, Etienne
    McInnes, Leland
    Healy, John
    Dutertre, Charles-Antoine
    Kwok, Immanuel W. H.
    Ng, Lai Guan
    Ginhoux, Florent
    Newell, Evan W.
    [J]. NATURE BIOTECHNOLOGY, 2019, 37 (01) : 38 - +
  • [9] T-cell/histiocyte-rich large B-cell lymphomas and classical diffuse large B-cell lymphomas have similar outcome after chemotherapy: A matched-control analysis
    Bouabdallah, R
    Mounier, N
    Guettier, C
    Molina, T
    Ribrag, V
    Thieblemont, C
    Sonet, A
    Delmer, A
    Belhadj, K
    Gaulard, P
    Gisselbrecht, C
    Xerri, L
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 2003, 21 (07) : 1271 - 1277
  • [10] Topological analysis reveals a PD-L1-associated microenvironmental niche for Reed-Sternberg cells in Hodgkin lymphoma
    Carey, Christopher D.
    Gusenleitner, Daniel
    Lipschitz, Mikel
    Roemer, Margaretha G. M.
    Stack, Edward C.
    Gjini, Evisa
    Hu, Xihao
    Redd, Robert
    Freeman, Gordon J.
    Neuberg, Donna
    Hodi, F. Stephen
    Liu, Xiaole Shirley
    Shipp, Margaret A.
    Rodig, Scott J.
    [J]. BLOOD, 2017, 130 (22) : 2420 - 2430