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

Author

Listed:
  • 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
    Fudan University)

  • Francesco M. Marincola

    (AbbVie Biotherapeutics)

  • John D. Heiss

    (National Institutes of Health)

  • Mark R. Gilbert

    (National Institutes of Health)

  • Rongze Lu

    (MedImmune
    AbbVie Biotherapeutics)

  • Zhengping Zhuang

    (National Institutes of Health
    National Institutes of Health)

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.

Suggested Citation

  • 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 & Zhengping Zhuang, 2018. "Pharmacologic inhibition of protein phosphatase-2A achieves durable immune-mediated antitumor activity when combined with PD-1 blockade," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04425-z
    DOI: 10.1038/s41467-018-04425-z
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