Inhibition of phospholipase D1 induces immunogenic cell death and potentiates cancer immunotherapy in colorectal cancer

Abstract

Phospholipase D (PLD) is a potential therapeutic target against cancer. However, the contribution of PLD inhibition to the antitumor response remains unknown. We developed a potent and selective PLD1 inhibitor based on computer-aided drug design. The inhibitor enhanced apoptosis in colorectal cancer (CRC) cells but not in normal colonic cells, and in vitro cardiotoxicity was not observed. The inhibitor downregulated the Wnt/β-catenin signaling pathway and reduced the migration, invasion, and self-renewal capacity of CRC cells. In cancer, therapeutic engagement of immunogenic cell death (ICD) leads to more effective responses by eliciting the antitumor immunity of T cells. The CRC cells treated with the inhibitor showed hallmarks of ICD, including downregulation of “do not eat-me” signals (CD24, CD47, programmed cell death ligand 1 [PD-L1]), upregulation of “eat-me” signal (calreticulin), release of high-mobility group Box 1, and ATP. PLD1 inhibition subsequently enhanced the phagocytosis of cancer cells by macrophages through the surface expression of costimulatory molecules; as a result, the cancer cells were more susceptible to cytotoxic T-cell-mediated killing. Moreover, PLD1 inhibition attenuated colitis-associated CRC and orthotopically injected tumors, probably by controlling multiple pathways, including Wnt signaling, phagocytosis checkpoints, and immune signaling. Furthermore, combination therapy with a PLD1 inhibitor and an anti-PD-L1 antibody further enhanced tumor regression via immune activation in the tumor environment. Collectively, in this study, PLD1 was identified as a critical regulator of the tumor microenvironment in colorectal cancer, suggesting the potential of PLD1 inhibitors for cancer immunotherapy based on ICD and immune activation. PLD1 inhibitors may act as promising immune modulators in antitumor treatment via ICD.

An overview of the mechanisms and potential roles of extracellular vesicles in septic shock

“…Urbahn et al found that TNF-a and IL-6 were reduced in the plasma of septic shock mice knocked out of the PLD1 gene, and mortality was also lesser (64). Hwang et al developed A3373, a potent inhibitor of PLD1, and this inhibitor was found to selectively bind to PLD1 to inhibit PLD1 activity (65). In our opinion, this inhibitor may also be effective in treating septic shock.…”

Clinical application of immunogenic cell death inducers in cancer immunotherapy: turning cold tumors hot

“…They also demonstrated that combining SR-4835 with anti-PD-1 can significantly inhibit tumor growth, providing a potential combination therapy for breast cancer ( Li et al, 2020 ). Hwang et al (2022) designed a phospholipase D (PLD) inhibitor to induce ICD to regulate TME in colorectal cancer, expecting to offer a promising strategy through this target drug. Moreover, researchers developed a novel fluorinated mitochondria-disrupting helical polypeptide to elicit mitochondrial dysfunction in murine colon adenocarcinoma CT26 cells.…”

Phospholipase D, a Novel Therapeutic Target Contributes to the Pathogenesis of Neurodegenerative and Neuroimmune Diseases

“…PLD1 has been identified as a cell mobility regulator. The absence of PLD1 in vitro models resulted in decreased blood–brain barrier and chemokine-induced lymphocyte static adherence to intercellular adhesion molecule 1 and vascular cell adhesion molecule 1, as well as reduced cell migration and motility [ 78 ]. The disease severity was reduced in experimental allergic encephalomyelitis (EAE) mice lacking PLD1 [ 79 ].…”