Pharmacologic inhibition of protein phosphatase-2A achieves durable immune-mediated antitumor activity when combined with PD-1 blockade

被引：64

作者：

Ho, Winson S. ^{[1
]}

Wang, Herui ^{[2
]}

Maggio, Dominic ^{[1
]}

Kovach, John S. ^{[3
]}

Zhang, Qi ^{[2
]}

Song, Qi ^{[2
,4
]}

Marincola, Francesco M. ^{[5
]}

Heiss, John D. ^{[1
]}

Gilbert, Mark R. ^{[2
]}

Lu, Rongze ^{[5
,6
]}

Zhuang, Zhengping ^{[1
,2
]}

机构：

[1] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA

[2] NCI, Neurooncol Branch, NIH, Bethesda, MD 20892 USA

[3] Lixte Biotechnol Holdings Inc, East Setauket, NY 11733 USA

[4] Fudan Univ, Zhongshan Hosp, Dept Pathol, Shanghai 200032, Peoples R China

[5] AbbVie Biotherapeut, Redwood City, CA 94063 USA

[6] MedImmune, Gaithersburg, MD 20878 USA

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

美国国家卫生研究院;

关键词：

T-CELL; OKADAIC ACID; CHECKPOINT BLOCKADE; SOLID TUMORS; IMMUNOTHERAPY TARGETS; UNTREATED MELANOMA; 2A INHIBITION; PHASE-I; CANCER; PP2A;

D O I：

10.1038/s41467-018-04425-z

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：

Mounting evidence suggests that inhibition of protein phosphatase-2A (PP2A), a serine/threonine phosphatase, could enhance anticancer immunity. However, drugs targeting PP2A are not currently available. Here, we report that a PP2A inhibitor, LB-100, when combined with anti-PD-1 (aPD-1) blockade can synergistically elicit a durable immune-mediated antitumor response in a murine CT26 colon cancer model. This effect is T-cell dependent, leading to regression of a significant proportion of tumors. Analysis of tumor lymphocytes demonstrates enhanced effector T-cell and reduced suppressive regulatory T-cell infiltration. Clearance of tumor establishes antigen-specific secondary protective immunity. A synergistic effect of LB-100 and aPD-1 blockade is also observed in B16 melanoma model. In addition, LB-100 activates the mTORC1 signaling pathway resulting in decreased differentiation of naive CD4 cells into regulatory T cells. There is also increased expression of Th1 and decreased expression of Th2 cytokines. These data highlight the translational potential of PP2A inhibition in combination with checkpoint inhibition.

引用

页数：15

共 41 条

[1] Phosphatase PP2A is requisite for the function of regulatory T cells [J].

Apostolidis, Sokratis A. ;

Rodriguez-Rodriguez, Noe ;

Suarez-Fueyo, Abel ;

Dioufa, Nikolina ;

Ozcan, Esra ;

Crispin, Jose C. ;

Tsokos, Maria G. ;

Tsokos, George C. .

NATURE IMMUNOLOGY, 2016, 17 (05) :556-+

[2] Inhibition of Protein Phosphatase 2A Enhances Cytotoxicity and Accessibility of Chemotherapeutic Drugs to Hepatocellular Carcinomas [J].

Bai, Xue-Li ;

Zhang, Qi ;

Ye, Long-Yun ;

Hu, Qi-Da ;

Fu, Qi-Han ;

Zhi, Xiao ;

Su, Wei ;

Su, Ri-Ga ;

Ma, Tao ;

Chen, Wei ;

Xie, Shang-Zhi ;

Chen, Cong-Lin ;

Liang, Ting-Bo .

MOLECULAR CANCER THERAPEUTICS, 2014, 13 (08) :2062-2072

[3] Inhibition of protein phosphatase 2A sensitizes pancreatic cancer to chemotherapy by increasing drug perfusion via HIF-1α-VEGF mediated angiogenesis [J].

Bai, Xueli ;

Zhi, Xiao ;

Zhang, Qi ;

Liang, Feng ;

Chen, Wei ;

Liang, Chao ;

Hu, Qida ;

Sun, Xu ;

Zhuang, Zhengping ;

Liang, Tingbo .

CANCER LETTERS, 2014, 355 (02) :281-287

[4] Phase I Study of Single-Agent Anti-Programmed Death-1 (MDX-1106) in Refractory Solid Tumors: Safety, Clinical Activity, Pharmacodynamics, and Immunologic Correlates [J].

Brahmer, Julie R. ;

Drake, Charles G. ;

Wollner, Ira ;

Powderly, John D. ;

Picus, Joel ;

Sharfman, William H. ;

Stankevich, Elizabeth ;

Pons, Alice ;

Salay, Theresa M. ;

McMiller, Tracee L. ;

Gilson, Marta M. ;

Wang, Changyu ;

Selby, Mark ;

Taube, Janis M. ;

Anders, Robert ;

Chen, Lieping ;

Korman, Alan J. ;

Pardoll, Drew M. ;

Lowy, Israel ;

Topalian, Suzanne L. .

JOURNAL OF CLINICAL ONCOLOGY, 2010, 28 (19) :3167-3175

[5] The Protein Phosphatase 2A Inhibitor LB100 Sensitizes Ovarian Carcinoma Cells to Cisplatin-Mediated Cytotoxicity [J].

Chang, Ki-Eun ;

Wei, Bih-Rong ;

Madigan, James P. ;

Hall, Matthew D. ;

Simpson, R. Mark ;

Zhuang, Zhengping ;

Gottesman, Michael M. .

MOLECULAR CANCER THERAPEUTICS, 2015, 14 (01) :90-100

[6] mTOR signaling, Tregs and immune modulation [J].

Chapman, Nicole M. ;

Chi, Hongbo .

IMMUNOTHERAPY, 2014, 6 (12) :1295-1311

[7] Oncology Meets Immunology: The Cancer-Immunity Cycle [J].

Chen, Daniel S. ;

Mellman, Ira .

IMMUNITY, 2013, 39 (01) :1-10

[8] Safety, Tolerability, and Preliminary Activity of LB-100, an Inhibitor of Protein Phosphatase 2A, in Patients with Relapsed Solid Tumors: An Open-Label, Dose Escalation, First-in-Human, Phase I Trial [J].

Chung, Vincent ;

Mansfield, Aaron S. ;

Braiteh, Fadi ;

Richards, Donald ;

Durivage, Henry ;

Ungerleider, Richard S. ;

Johnson, Francis ;

Kovach, John S. .

CLINICAL CANCER RESEARCH, 2017, 23 (13) :3277-3284

[9] PP2A's restraint of mTOR is critical for Treg cell activity [J].

Delgoffe, Greg M. .

NATURE IMMUNOLOGY, 2016, 17 (05) :478-479

[10] The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2 [J].

Delgoffe, Greg M. ;

Pollizzi, Kristen N. ;

Waickman, Adam T. ;

Heikamp, Emily ;

Meyers, David J. ;

Horton, Maureen R. ;

Xiao, Bo ;

Worley, Paul F. ;

Powell, Jonathan D. .

NATURE IMMUNOLOGY, 2011, 12 (04) :295-U117

← 1 2 3 4 5 →