RRC ID 66959
Author Eino D, Tsukada Y, Naito H, Kanemura Y, Iba T, Wakabayashi T, Muramatsu F, Kidoya H, Arita H, Kagawa N, Fujimoto Y, Takara K, Kishima H, Takakura N.
Title LPA4-Mediated Vascular Network Formation Increases the Efficacy of Anti-PD-1 Therapy against Brain Tumors.
Journal Cancer Res
Abstract : The structure and function of tumor blood vessels profoundly affects the tumor microenvironment. Signals mediated through the lysophosphatidic acid receptor 4 (LPA4) promote vascular network formation to restore normal vascular barrier function in subcutaneous tumors and thus improve drug delivery. However, the characteristics of the vasculature vary by organ and tumor types, and how drug delivery and leukocyte trafficking are affected by modification of vascular function by LPA in different cancers is unclear. Here, we show that LPA4 activation promotes the formation of fine vascular structures in brain tumors. RhoA/ROCK signaling contributed to LPA-induced endothelial cell-cell adhesion, and RhoA/ROCK activity following LPA4 stimulation regulated expression of VCAM-1. This resulted in increased lymphocyte infiltration into the tumor. LPA improved delivery of exogenous IgG into brain tumors and enhanced the anticancer effect of anti-programmed cell death-1 antibody therapy. These results indicate the effects of LPA on vascular structure and function apply not only to chemotherapy but also to immunotherapy. SIGNIFICANCE: These findings demonstrate that lysophosphatidic acid, a lipid mediator, promotes development of a fine capillary network in brain tumors by inducing tightening of endothelial cell-to-cell adhesion, facilitating improved drug delivery, and lymphocyte penetration.
Volume 78(23)
Pages 6607-6620
Published 2018-12-1
DOI 10.1158/0008-5472.CAN-18-0498
PII 0008-5472.CAN-18-0498
PMID 30301839
MeSH Animals Antineoplastic Agents, Immunological / pharmacology* Brain Neoplasms / drug therapy Brain Neoplasms / genetics* Brain Neoplasms / metabolism* Brain Neoplasms / pathology Cell Line, Tumor Disease Models, Animal Endothelial Cells / metabolism Female Lymphocytes, Tumor-Infiltrating / immunology Lymphocytes, Tumor-Infiltrating / metabolism Mice Mice, Knockout NF-kappa B / metabolism Neovascularization, Pathologic / drug therapy Neovascularization, Pathologic / genetics* Programmed Cell Death 1 Receptor / antagonists & inhibitors* RNA, Small Interfering / genetics Receptors, Purinergic / genetics* Receptors, Purinergic / metabolism Signal Transduction Treatment Outcome Vascular Cell Adhesion Molecule-1 / metabolism Xenograft Model Antitumor Assays rho-Associated Kinases / metabolism rhoA GTP-Binding Protein / metabolism
IF 9.727
Human and Animal Cells LLC(RCB0558) OP9(RCB1124)