Pharmacologic inhibition of protein phosphatase-2A achieves durable immune-mediated antitumor activity when combined with PD-1 blockade.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 29844427.
- Also identified by DOI 10.1038/s41467-018-04425-z and PMC identifier 5974350.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Antineoplastic Agents
- Bridged Bicyclo Compounds, Heterocyclic
- Colonic Neoplasms
- Immunotherapy
- Lymphocytes, Tumor-Infiltrating
- Melanoma, Experimental
- Piperazines
- Programmed Cell Death 1 Receptor
- Protein Phosphatase 2
- T-Lymphocytes, Regulatory