A combination of protein phosphatase 2A inhibition and checkpoint immunotherapy: a perfect storm

Mol Oncol. 2024 Oct;18(10):2333-2337. doi: 10.1002/1878-0261.13687. Epub 2024 Jun 26.

Abstract

Immune checkpoint blockade has emerged as a potent new tool in the war on cancer. However, only a subset of cancer patients benefit from this therapeutic modality, sparking a search for combination therapies to increase the fraction of responding patients. We argue here that inhibition of protein phosphatase 2A (PP2A) is a promising approach to increase responses to immune checkpoint blockade and other therapies that rely on the presence of tumor-reactive T cells. Inhibition of PP2A increases neoantigen expression on tumor cells, activates the cGAS/STING pathway, suppresses regulatory T cells, and increases cytotoxic T cell activation. In preclinical models, inhibition of PP2A synergizes with immune checkpoint blockade and emerging evidence indicates that patients who have tumors with mutations in PP2A respond better to immune checkpoint blockade. Therefore, inhibition of PP2A activity may be an effective way to sensitize cancer cells to immune checkpoint blockade and cell-based therapies using tumor-reactive T cells.

Keywords: PP2A; TIL therapy; checkpoint inhibitor.

Publication types

  • Review

MeSH terms

  • Animals
  • Humans
  • Immune Checkpoint Inhibitors* / pharmacology
  • Immune Checkpoint Inhibitors* / therapeutic use
  • Immunotherapy* / methods
  • Neoplasms* / drug therapy
  • Neoplasms* / immunology
  • Neoplasms* / therapy
  • Protein Phosphatase 2* / antagonists & inhibitors
  • Protein Phosphatase 2* / metabolism

Substances

  • Protein Phosphatase 2
  • Immune Checkpoint Inhibitors