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

Nature Communications
Winson S HoZhengping Zhuang

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.

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Citations

Mar 27, 2020·Journal for Immunotherapy of Cancer·Lorenzo GalluzziFrancesco M Marincola
Jun 27, 2019·Journal for Immunotherapy of Cancer·Mathieu GrapinCéline Mirjolet
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Aug 18, 2021·The Journal of Clinical Investigation·Feixiang WangQiang Zou
Jul 14, 2021·Molecular Cancer Therapeutics·Tamara MirzapoiazovaRavi Salgia

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Datasets Mentioned

BETA
GM-CSF

Methods Mentioned

BETA
xenograft
FACS
flow cytometry
transgenic
PCR
Assay
ELISA

Software Mentioned

GraphPad Prism

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