title: Cancer-associated fibroblast suppresses killing activity of natural killer cells through downregulation of poliovirus receptor (PVR/CD155), a ligand of activating NK receptor.
abstract: Cancer-associated fibroblasts (CAFs) play an important role in cancer expansion and progression in tumor microenvironment (TME), via both direct and indirect interactions. Natural killer (NK) cells play a crucial role in anticancer immunity. We investigated the inhibitory effects of CAFs on NK cell activity. CAFs were isolated from endometrial cancer tissue, while normal endometrial fibroblasts (NEFs) were obtained from normal endometrium with no pathological abnormality. NK cells were obtained from allogenic healthy volunteers. CAFs or NEFs were co-cultured at an NK/fibroblast ratio of 1:1 with or without inserted membrane. For NK cell activity, K562 cells were cultured as target cells. NK cell-killing activity was determined by calculating the ratio of PI-positive K562 cells in the presence of NK cells co-cultured with fibroblasts versus NK cells alone. To examine whether NK cell activity was suppressed by IDO pathway, we inhibited IDO activity using the IDO inhibitor 1-MT. We demonstrated that CAFs derived from endometrial cancer induced greater suppression of the killing activity of allogenic NK cells compared with normal endometrial fibroblasts (NEFs). The suppression of NK cell activity by CAFs was inhibited when a membrane was inserted between the CAFs and NK cells, but not by 1-MT, an inhibitor of IDO. We focused on receptor-ligand interactions between CAFs and NK cell and found that cell-surface poliovirus receptor (PVR/CD155), a ligand of activating NK receptor DNAM-1, was downregulated in the CAFs compared with NEFs. To confirm whether PVR downregulation results in the decrease of NK cell-killing activity, PVR expression in NEFs was knocked down using siRNA against PVR (PVRsi). NK cell activity was suppressed by co-culture with PVR-knockdown NEFs, to a similar extent than CAF-induced suppression. CAFs showed increased suppression of NK cell-killing activity compared with NEFs, due to decreased PVR cell surface expression, a ligand of an NK activating receptor. This study demonstrated a novel mechanism of suppression of NK cell activity by CAFs in the TME.
authors: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Tomoko
authors: T
authors: Inoue
authors: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Katsuyuki
authors: K
authors: Adachi
authors: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Kei
authors: K
authors: Kawana
authors: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Ayumi
authors: A
authors: Taguchi
authors: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Takeshi
authors: T
authors: Nagamatsu
authors: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Asaha
authors: A
authors: Fujimoto
authors: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Kensuke
authors: K
authors: Tomio
authors: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Aki
authors: A
authors: Yamashita
authors: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Satoko
authors: S
authors: Eguchi
authors: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Haruka
authors: H
authors: Nishida
authors: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Hiroe
authors: H
authors: Nakamura
authors: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Masakazu
authors: M
authors: Sato
authors: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Mitsuyo
authors: M
authors: Yoshida
authors: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Takahide
authors: T
authors: Arimoto
authors: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Osamu
authors: O
authors: Wada-Hiraike
authors: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Katsutoshi
authors: K
authors: Oda
authors: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Yutaka
authors: Y
authors: Osuga
authors: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Tomoyuki
authors: T
authors: Fujii
mesh_terms: D000072645:Cancer-Associated Fibroblasts / Q000166:cytology / Q000502:physiology*; D018920:Coculture Techniques; D015536:Down-Regulation; D016889:Endometrial Neoplasms / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000166:cytology / Q000502:physiology*; D011991:Receptors, Virus / Q000378:metabolism*
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D011991:Receptors, Virus; C066100:poliovirus receptor