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; Zhengping Zhuang

doi:10.1038/s41467-018-04425-z

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

Nat Commun. 2018 May 29;9(1):2126. doi: 10.1038/s41467-018-04425-z.

Authors

Winson S Ho¹, Herui Wang², Dominic Maggio¹, John S Kovach³, Qi Zhang², Qi Song^{2

4}, Francesco M Marincola⁵, John D Heiss¹, Mark R Gilbert², Rongze Lu^{6

7}, Zhengping Zhuang^{8

9}

Affiliations

¹ Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA.
² Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
³ Lixte Biotechnology Holdings, Inc., East Setauket, NY, 11733, USA.
⁴ Department of Pathology, Zhongshan Hospital, Fudan University, 200032, Shanghai, People's Republic of China.
⁵ AbbVie Biotherapeutics, Redwood City, CA, 94063, USA.
⁶ MedImmune, Gaithersburg, MD, 20878, USA. [email protected].
⁷ AbbVie Biotherapeutics, Redwood City, CA, 94063, USA. [email protected].
⁸ Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA. [email protected].
⁹ Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. [email protected].

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.

Publication types

Research Support, N.I.H., Intramural

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Antineoplastic Combined Chemotherapy Protocols
Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
CD8-Positive T-Lymphocytes / immunology
Cell Line, Tumor
Colonic Neoplasms / immunology
Colonic Neoplasms / therapy*
Female
Humans
Immunotherapy / methods*
Lymphocyte Activation / drug effects
Lymphocyte Activation / immunology
Lymphocytes, Tumor-Infiltrating / immunology*
Mechanistic Target of Rapamycin Complex 1 / metabolism
Melanoma, Experimental / immunology
Melanoma, Experimental / therapy*
Mice
Mice, Inbred BALB C
Piperazines / pharmacology*
Programmed Cell Death 1 Receptor / antagonists & inhibitors*
Protein Phosphatase 2 / antagonists & inhibitors*
Signal Transduction / drug effects
Signal Transduction / immunology
T-Lymphocytes, Regulatory / immunology*
Th1 Cells / immunology
Th2 Cells / immunology

Substances

Antineoplastic Agents
Bridged Bicyclo Compounds, Heterocyclic
LB100
Pdcd1 protein, mouse
Piperazines
Programmed Cell Death 1 Receptor
Mechanistic Target of Rapamycin Complex 1
Protein Phosphatase 2