LPA4-Mediated Vascular Network Formation Increases the Efficacy of Anti-PD-1 Therapy against Brain Tumors

• Published in: Cancer research (Chicago, Ill.) Ill.), 2018-12, Vol.78 (23), p.6607-6620
• Main Authors: Eino, Daisuke, Tsukada, Yohei, Naito, Hisamichi, Kanemura, Yonehiro, Iba, Tomohiro, Wakabayashi, Taku, Muramatsu, Fumitaka, Kidoya, Hiroyasu, Arita, Hideyuki, Kagawa, Naoki, Fujimoto, Yasunori, Takara, Kazuhiro, Kishima, Haruhiko, Takakura, Nobuyuki
• Format: Article
• Language: English
• Subjects: 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; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - genetics; NF-kappa B - metabolism; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Receptors, Purinergic - genetics; Receptors, Purinergic - metabolism; rho-Associated Kinases - metabolism; rhoA GTP-Binding Protein - metabolism; RNA, Small Interfering - genetics; Signal Transduction; Treatment Outcome; Vascular Cell Adhesion Molecule-1 - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-18-0498

: 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.