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

• Published in: Experimental & molecular medicine Vol. 54; no. 9; pp. 1563 - 1576
• Main Authors: Hwang, Won Chan, Song, Doona, Lee, Hyesung, Oh, Changmok, Lim, Seong Hun, Bae, Hyeon Jeong, Kim, Nam Doo, Han, Gyoonhee, Min, Do Sik
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2022; Springer Nature B.V; 생화학분자생물학회
• Subjects: 631/67/1504/1885/1393; 631/67/327; Adenosine Triphosphate; Animal models; Antitumor activity; Apoptosis; Biomedical and Life Sciences; Biomedicine; Calreticulin; Cancer; Cancer immunotherapy; CD47 Antigen - metabolism; Cell death; Colitis; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Costimulator; Cytotoxicity; Drug development; Drug resistance; Enzymes; HMGB1 protein; Humans; Immune system; Immunogenic Cell Death; Immunogenicity; Immunomodulation; Immunotherapy; Leukocyte migration; Ligands; Lymphocytes T; Macrophages; Medical Biochemistry; Molecular Medicine; PD-L1 protein; Phagocytosis; Phospholipase D - metabolism; Signal transduction; Stem Cells; Tumor Microenvironment; Tumors; Wnt Signaling Pathway; 생화학
• ISSN: 2092-6413; 1226-3613; 2092-6413
• DOI: 10.1038/s12276-022-00853-6

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. Colorectal cancer: Enzyme inhibition enhances immunotherapy A novel drug that can inhibit an enzyme involved in colorectal cancer progression shows promise in trials on mouse models. The phospholipase D1 (PLD1) enzyme reinforces a critical signaling pathway that promotes cancer progression and drug resistance. Using computer-aided drug design, South Korean researchers led by Do Sik Min and Gyoonhee Han at Yonsei University in Incheon and Seoul, respectively, have developed a drug that specifically binds to and inhibits PLD1. In trials, the researchers observed downregulation of PLD1’s associated signaling pathway, and reductions in the ability of colorectal cancer cells to migrate, invade and replicate. The drug suppressed the cancer cells’ “don’t-eat-me” signals and upregulated “eat-me” signals, triggering improved responses from the immune system. The drug was even more effective when used in combination with an immunotherapy agent.