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

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.

Fig. 1

PP2A inhibition may enhance the efficacy of immune‐based cancer therapies. PP2A inhibition affects both cancer cells and immune cells. In cancer cells, PP2A enhances neoantigen expression in part by promoting alternative RNA splicing and genomic instability. By increasing the number of targets that are recognizable by endogenous immune cells, PP2A inhibition may increase the number of tumor‐infiltrating lymphocytes (TIL). In immune cells, inhibiting PP2A enhances immune activation through many mechanisms, including decreasing the number and immunosuppressive activity of both regulatory T cells (Tregs) and tumor‐associated macrophages (TAMs). PP2A inhibition also increases the activation of cytotoxic T cells. Therefore, PP2A inhibition increases the endogenous antitumor immune response, which may be leveraged for combination strategies that require an endogenous pool of tumor‐reactive T cells, including TIL therapy and checkpoint therapy. Figure generated in BioRender.com.