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Combination therapy for hepatocellular carcinoma with diacylglycerol kinase alpha inhibition and anti-programmed cell death-1 ligand blockade.

Abstract
Activation of diacylglycerol kinase alpha (DGKα) augments proliferation and suppresses apoptosis of cancer cells and induces T lymphocyte anergy. We investigated the dual effects of DGKα inhibition on tumorigenesis and anti-tumor immunity with the aim of establishing a novel therapeutic strategy for cancer. We examined the effects of a DGKα inhibitor (DGKAI) on liver cancer cell proliferation and cytokine production by immune cells in vitro and on tumorigenesis and host immunity in a hepatocellular carcinoma (HCC) mouse model. Oral DGKAI significantly suppressed tumor growth and prolonged survival in model mice. Tumor infiltration of T cells and dendritic cells was also enhanced in mice treated with DGKAI, and the production of cytokines and cytotoxic molecules by CD4+ and CD8+ T cells was increased. Depletion of CD8+ T cells reduced the effect of DGKAI. Furthermore, interferon-γ stimulation augmented the expression of programmed cell death-1 ligand (PD-L1) on cancer cells, and DGKAI plus an anti-PD-L1 antibody strongly suppressed the tumor growth. These results suggest that DGKα inhibition may be a promising new treatment strategy for HCC.
AuthorsNaoki Okada, Ko Sugiyama, Shunsuke Shichi, Yasuhito Shirai, Kaoru Goto, Fumio Sakane, Hidemitsu Kitamura, Akinobu Taketomi
JournalCancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 71 Issue 4 Pg. 889-903 (Apr 2022) ISSN: 1432-0851 [Electronic] Germany
PMID34482409 (Publication Type: Journal Article)
Copyright© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Chemical References
  • B7-H1 Antigen
  • Ligands
  • Diacylglycerol Kinase
Topics
  • Animals
  • B7-H1 Antigen (metabolism)
  • CD8-Positive T-Lymphocytes
  • Carcinoma, Hepatocellular (pathology)
  • Diacylglycerol Kinase
  • Ligands
  • Liver Neoplasms
  • Mice

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