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

Winson S. Ho, Herui Wang, Dominic Maggio, John S. Kovach, Qi Zhang, Qi Song, Francesco M. Marincola, John D. Heiss, Mark R. Gilbert, Rongze Lu () and Zhengping Zhuang ()
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Winson S. Ho: National Institutes of Health
Herui Wang: National Institutes of Health
Dominic Maggio: National Institutes of Health
John S. Kovach: Lixte Biotechnology Holdings, Inc.
Qi Zhang: National Institutes of Health
Qi Song: National Institutes of Health
Francesco M. Marincola: AbbVie Biotherapeutics
John D. Heiss: National Institutes of Health
Mark R. Gilbert: National Institutes of Health
Rongze Lu: MedImmune
Zhengping Zhuang: National Institutes of Health

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-04425-z

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