Acquired cancer cell resistance to T cell bispecific antibodies and CAR T targeting HER2 through JAK2 down-modulation

被引:39
作者
Arenas, Enrique J. [1 ,2 ]
Martinez-Sabadell, Alex [1 ]
Rius Ruiz, Irene [1 ,2 ]
Roman Alonso, Macarena [1 ]
Escorihuela, Marta [1 ]
Luque, Antonio [1 ]
Fajardo, Carlos Alberto [3 ]
Gros, Alena [3 ]
Klein, Christian [4 ]
Arribas, Joaquin [1 ,2 ,5 ,6 ,7 ]
机构
[1] Vall dHebron Inst Oncol VHIO, Vall dHebron Barcelona Hosp Campus, Preclin Res Program, Barcelona 08035, Spain
[2] Ctr Investigac Biomed Red Canc CIBERONC, Madrid 28029, Spain
[3] VHIO, Vall dHebron Barcelona Hosp Campus, Tumor Immunol & Immunotherapy Grp, Barcelona 08035, Spain
[4] Roche Innovat Ctr Zurich, Roche Pharmaceut Res & Early Dev, CH-8952 Schlieren, Switzerland
[5] Univ Autonoma Barcelona UAB, Dept Biochem & Mol Biol, Bellaterra 08193, Spain
[6] IMIM Hosp del Mar Med Res Inst, Canc Res Program, Barcelona 08003, Spain
[7] Inst Catalana Recerca & Estudis Avancats ICREA, Barcelona 08010, Spain
关键词
SINGLE-CHAIN ANTIBODY; SYNAPSES; AFFINITY; BETA;
D O I
10.1038/s41467-021-21445-4
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Immunotherapy has raised high expectations in the treatment of virtually every cancer. Many current efforts are focused on ensuring the efficient delivery of active cytotoxic cells to tumors. It is assumed that, once these active cytotoxic cells are correctly engaged to cancer cells, they will unfailingly eliminate the latter, provided that inhibitory factors are in check. T cell bispecific antibodies (TCBs) and chimeric antigen receptors (CARs) offer an opportunity to test this assumption. Using TCB and CARs directed against HER2, here we show that disruption of interferon-gamma signaling confers resistance to killing by active T lymphocytes. The kinase JAK2, which transduces the signal initiated by interferon-gamma, is a component repeatedly disrupted in several independently generated resistant models. Our results unveil a seemingly widespread strategy used by cancer cells to resist clearance by redirected lymphocytes. In addition, they open the possibility that long-term inhibition of interferon-gamma signaling may impair the elimination phase of immunoediting and, thus, promote tumor progression. Several mechanisms of resistance to T cell-engaging therapies have been described for solid tumors. Here, by using T cell bispecific antibodies and chimeric antigen receptors (CAR) T cells targeting HER2, the authors show that cancer cell intrinsic disruption of interferon-gamma signalling, including downregulation of JAK2, confers resistance to T-cell mediated cytotoxicity.
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页数:13
相关论文
共 39 条
[1]   Interferon γ and Its Important Roles in Promoting and Inhibiting Spontaneous and Therapeutic Cancer Immunity [J].
Alspach, Elise ;
Lussier, Danielle M. ;
Schreiber, Robert D. .
COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY, 2019, 11 (03)
[2]   ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics [J].
Arteaga, Carlos L. ;
Engelman, Jeffrey A. .
CANCER CELL, 2014, 25 (03) :282-303
[3]   Killing Mechanisms of Chimeric Antigen Receptor (CAR) T Cells [J].
Benmebarek, Mohamed-Reda ;
Karches, Clara Helke ;
Cadilha, Bruno Loureiro ;
Lesch, Stefanie ;
Endres, Stefan ;
Kobold, Sebastian .
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2019, 20 (06)
[4]   JAK2 inhibitors for myeloproliferative neoplasms: what is next? [J].
Bose, Prithviraj ;
Verstovsek, Srdan .
BLOOD, 2017, 130 (02) :115-125
[5]   FDA Approval Summary: Axicabtagene Ciloleucel for Relapsed or Refractory Large B-cell Lymphoma [J].
Bouchkouj, Najat ;
Kasamon, Yvette L. ;
de Claro, R. Angelo ;
George, Bindu ;
Lin, Xue ;
Lee, Shiowjen ;
Blumenthal, Gideon M. ;
Bryan, Wilson ;
McKee, Amy E. ;
Pazdur, Richard .
CLINICAL CANCER RESEARCH, 2019, 25 (06) :1702-1708
[6]   Redirected T Cell Cytotoxicity in Cancer Therapy [J].
Clynes, Raphael A. ;
Desjarlais, John R. .
ANNUAL REVIEW OF MEDICINE, VOL 70, 2019, 70 :437-450
[7]   Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity [J].
Davenport, A. J. ;
Cross, R. S. ;
Watson, K. A. ;
Liao, Y. ;
Shi, W. ;
Prince, H. M. ;
Beavis, P. A. ;
Trapani, J. A. ;
Kershaw, M. H. ;
Ritchie, D. S. ;
Darcy, P. K. ;
Neeson, P. J. ;
Jenkins, M. R. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2018, 115 (09) :E2068-E2076
[8]   Identification of genes differentially regulated by interferon α, β, or γ using oligonucleotide arrays [J].
Der, SD ;
Zhou, AM ;
Williams, BRG ;
Silverman, RH .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (26) :15623-15628
[9]  
Goebeler M-E., 2020, Nat. Rev. Clin. Oncol, V16, P2825
[10]   Histone modifications at human enhancers reflect global cell-type-specific gene expression [J].
Heintzman, Nathaniel D. ;
Hon, Gary C. ;
Hawkins, R. David ;
Kheradpour, Pouya ;
Stark, Alexander ;
Harp, Lindsey F. ;
Ye, Zhen ;
Lee, Leonard K. ;
Stuart, Rhona K. ;
Ching, Christina W. ;
Ching, Keith A. ;
Antosiewicz-Bourget, Jessica E. ;
Liu, Hui ;
Zhang, Xinmin ;
Green, Roland D. ;
Lobanenkov, Victor V. ;
Stewart, Ron ;
Thomson, James A. ;
Crawford, Gregory E. ;
Kellis, Manolis ;
Ren, Bing .
NATURE, 2009, 459 (7243) :108-112