2. Academic Validation
  3. Inhibition of phospholipase D1 induces immunogenic cell death and potentiates cancer immunotherapy in colorectal cancer

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

  • Exp Mol Med. 2022 Sep;54(9):1563-1576. doi: 10.1038/s12276-022-00853-6.
Won Chan Hwang # 1,  Doona Song # 2 3,  Hyesung Lee # 1,  Changmok Oh 3,  Seong Hun Lim 1,  Hyeon Jeong Bae 1,  Nam Doo Kim 4,  Gyoonhee Han 5 6,  Do Sik Min 7 8
Affiliations

Affiliations

  • 1 Department of Pharmacy, Yonsei University, Incheon, 21983, Republic of Korea.
  • 2 Graduate Program of Industrial Pharmaceutical Science, Yonsei University, Incheon, 21983, Republic of Korea.
  • 3 Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea.
  • 4 Voronoi Bio Inc., 32 Songdokwahak-ro, Yeonsu-gu, Incheon, 21984, Republic of Korea.
  • 5 Department of Pharmacy, Yonsei University, Incheon, 21983, Republic of Korea. gyoonhee@yonsei.ac.kr.
  • 6 Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea. gyoonhee@yonsei.ac.kr.
  • 7 Department of Pharmacy, Yonsei University, Incheon, 21983, Republic of Korea. minds@yonsei.ac.kr.
  • 8 Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon, 21983, Republic of Korea. minds@yonsei.ac.kr.
  • # Contributed equally.
PMID: 36131027 DOI: 10.1038/s12276-022-00853-6
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.

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