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

• Published in: Nature communications Vol. 9; no. 1; pp. 2126 - 15
• Main Authors: Ho, Winson S., Wang, Herui, Maggio, Dominic, Kovach, John S., Zhang, Qi, Song, Qi, Marincola, Francesco M., Heiss, John D., Gilbert, Mark R., Lu, Rongze, Zhuang, Zhengping
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.05.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/31; 631/67/1059/2325; 631/67/580; 64; 64/110; 64/60; Animals; Anticancer properties; Antineoplastic Agents - pharmacology; Antineoplastic Combined Chemotherapy Protocols; Antitumor activity; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; CD4 antigen; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Colon; Colon cancer; Colonic Neoplasms - immunology; Colonic Neoplasms - therapy; Colorectal cancer; Cytokines; Drug delivery; Female; Humanities and Social Sciences; Humans; Immune clearance; Immunity; Immunoregulation; Immunosuppressive agents; Immunotherapy - methods; Infiltration; Kinases; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; Mechanistic Target of Rapamycin Complex 1 - metabolism; Melanoma; Melanoma, Experimental - immunology; Melanoma, Experimental - therapy; Metastases; Mice; Mice, Inbred BALB C; multidisciplinary; PD-1 protein; Pharmacology; Phosphatase; Phosphoprotein phosphatase; Piperazines - pharmacology; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Protein phosphatase; Protein Phosphatase 2 - antagonists & inhibitors; Protein-serine/threonine phosphatase; Proteins; Regression analysis; Science; Science (multidisciplinary); Serine; Signal transduction; Signal Transduction - drug effects; Signal Transduction - immunology; Synergistic effect; T-Lymphocytes, Regulatory - immunology; Th1 Cells - immunology; Th2 Cells - immunology; Threonine phosphatase; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-04425-z

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. Protein phosphatase 2A (PP2A) has been proposed as a target for cancer immunotherapy. Here the authors show that pharmacological inhibition of PP2A with a clinically-relevant inhibitor enhances response to immune checkpoint blockade in pre-clinical models of cancer, resulting in long lasting immunity.