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

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