PMID- 37146474
OWN - NLM
STAT- MEDLINE
DCOM- 20230522
LR  - 20230522
IS  - 1872-8332 (Electronic)
IS  - 0169-5002 (Linking)
VI  - 180
DP  - 2023 Jun
TI  - Combination therapy with anti-programmed cell death 1 antibody plus angiokinase 
      inhibitor exerts synergistic antitumor effect against malignant mesothelioma via 
      tumor microenvironment modulation.
PG  - 107219
LID - S0169-5002(23)00757-2 [pii]
LID - 10.1016/j.lungcan.2023.107219 [doi]
AB  - Malignant pleural mesothelioma (MPM) is an asbestos-related fatal malignant 
      neoplasm. Although there has been no reliable chemotherapeutic regimen other than 
      combination therapy of cisplatin and pemetrexed for two decades, combination of 
      ipilimumab plus nivolumab brought about a better outcome in patients with MPM. 
      Thus, cancer immunotherapy using immune checkpoint inhibitor (ICI) is expected to 
      play a central role in the treatment of MPM. To maximize the antitumor effect of 
      ICI, we evaluated whether nintedanib, an antiangiogenic agent, could augment the 
      antitumor effect of anti-programmed cell death 1 (PD-1) antibody (Ab). Although 
      nintedanib could not inhibit the proliferation of mesothelioma cells in vitro, it 
      significantly suppressed the growth of mesothelioma allografts in mice. Moreover, 
      combination therapy with anti-PD-1 Ab plus nintedanib reduced tumor burden more 
      dramatically compared with nintedanib monotherapy via inducing remarkable 
      necrosis in MPM allografts. Nintedanib did not promote the infiltration of 
      CD8(+) T cells within the tumor when used alone or in combination with anti-PD-1 
      Ab but it independently decreased the infiltration of tumor-associated 
      macrophages (TAMs). Moreover, immunohistochemical analysis and ex vivo study 
      using bone marrow-derived macrophages (BMDMs) showed that nintedanib could 
      polarize TAMs from M2 to M1 phenotype. These results indicated that nintedanib 
      had a potential to suppress protumor activity of TAMs both numerically and 
      functionally. On the other hand, ex vivo study revealed that nintedanib 
      upregulated the expression of PD-1 and PD-ligand 1 (PD-L1) in BMDMs and 
      mesothelioma cells, respectively, and exhibited the impairment of phagocytic 
      activity of BMDMs against mesothelioma cells. Co-administration of anti-PD-1 Ab 
      may reactivate phagocytic activity of BMDMs by disrupting nintedanib-induced 
      immunosuppressive signal via binding between PD-1 on BMDMs and PD-L1 on 
      mesothelioma cells. Collectively, combination therapy of anti-PD-1 Ab plus 
      nintedanib enhances the antitumor activity compared with respective monotherapy 
      and can become a novel therapeutic option for patients with MPM.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier B.V. All rights reserved.
FAU - Tada, Akio
AU  - Tada A
AD  - Department of Respiratory Medicine and Hematology, Hyogo Medical University, 
      Nishinomiya, Hyogo, Japan.
FAU - Minami, Toshiyuki
AU  - Minami T
AD  - Department of Respiratory Medicine and Hematology, Hyogo Medical University, 
      Nishinomiya, Hyogo, Japan; Department of Thoracic Oncology, Hyogo Medical 
      University, Nishinomiya, Hyogo, Japan. Electronic address: 
      to-minami@hyo-med.ac.jp.
FAU - Kitai, Hidemi
AU  - Kitai H
AD  - Department of Thoracic Oncology, Hyogo Medical University, Nishinomiya, Hyogo, 
      Japan.
FAU - Higashiguchi, Yoko
AU  - Higashiguchi Y
AD  - Department of Respiratory Medicine and Hematology, Hyogo Medical University, 
      Nishinomiya, Hyogo, Japan.
FAU - Tokuda, Mayuko
AU  - Tokuda M
AD  - Department of Respiratory Medicine and Hematology, Hyogo Medical University, 
      Nishinomiya, Hyogo, Japan.
FAU - Higashiyama, Tomoki
AU  - Higashiyama T
AD  - Department of Respiratory Medicine and Hematology, Hyogo Medical University, 
      Nishinomiya, Hyogo, Japan.
FAU - Negi, Yoshiki
AU  - Negi Y
AD  - Department of Respiratory Medicine and Hematology, Hyogo Medical University, 
      Nishinomiya, Hyogo, Japan; Department of Thoracic Oncology, Hyogo Medical 
      University, Nishinomiya, Hyogo, Japan.
FAU - Horio, Daisuke
AU  - Horio D
AD  - Department of Respiratory Medicine and Hematology, Hyogo Medical University, 
      Nishinomiya, Hyogo, Japan; Department of Thoracic Oncology, Hyogo Medical 
      University, Nishinomiya, Hyogo, Japan.
FAU - Nakajima, Yasuhiro
AU  - Nakajima Y
AD  - Department of Respiratory Medicine and Hematology, Hyogo Medical University, 
      Nishinomiya, Hyogo, Japan.
FAU - Otsuki, Taiichiro
AU  - Otsuki T
AD  - Department of Respiratory Medicine and Hematology, Hyogo Medical University, 
      Nishinomiya, Hyogo, Japan; Department of Thoracic Oncology, Hyogo Medical 
      University, Nishinomiya, Hyogo, Japan.
FAU - Mikami, Koji
AU  - Mikami K
AD  - Department of Respiratory Medicine and Hematology, Hyogo Medical University, 
      Nishinomiya, Hyogo, Japan; Department of Thoracic Oncology, Hyogo Medical 
      University, Nishinomiya, Hyogo, Japan.
FAU - Takahashi, Ryo
AU  - Takahashi R
AD  - Department of Respiratory Medicine and Hematology, Hyogo Medical University, 
      Nishinomiya, Hyogo, Japan; Department of Thoracic Oncology, Hyogo Medical 
      University, Nishinomiya, Hyogo, Japan.
FAU - Nakamura, Akifumi
AU  - Nakamura A
AD  - Department of Thoracic Surgery, Hyogo Medical University, Nishinomiya, Hyogo, 
      Japan.
FAU - Kitajima, Kazuhiro
AU  - Kitajima K
AD  - Department of Radiology, Hyogo Medical University, Nishinomiya, Hyogo, Japan.
FAU - Ohmuraya, Masaki
AU  - Ohmuraya M
AD  - Department of Genetics, Hyogo Medical University, Nishinomiya, Japan.
FAU - Kuribayashi, Kozo
AU  - Kuribayashi K
AD  - Department of Respiratory Medicine and Hematology, Hyogo Medical University, 
      Nishinomiya, Hyogo, Japan; Department of Thoracic Oncology, Hyogo Medical 
      University, Nishinomiya, Hyogo, Japan.
FAU - Kijima, Takashi
AU  - Kijima T
AD  - Department of Respiratory Medicine and Hematology, Hyogo Medical University, 
      Nishinomiya, Hyogo, Japan; Department of Thoracic Oncology, Hyogo Medical 
      University, Nishinomiya, Hyogo, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230426
PL  - Ireland
TA  - Lung Cancer
JT  - Lung cancer (Amsterdam, Netherlands)
JID - 8800805
RN  - G6HRD2P839 (nintedanib)
RN  - 0 (Indoles)
RN  - 0 (Programmed Cell Death 1 Receptor)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Angiogenesis Inhibitors)
RN  - 0 (Antibodies, Monoclonal)
SB  - IM
MH  - Humans
MH  - Female
MH  - Animals
MH  - Mice
MH  - Cell Line, Tumor
MH  - Mice, Inbred C57BL
MH  - *Mesothelioma, Malignant/drug therapy
MH  - *Antineoplastic Combined Chemotherapy Protocols/therapeutic use
MH  - *Indoles/therapeutic use
MH  - *Programmed Cell Death 1 Receptor/antagonists & inhibitors
MH  - *Protein Kinase Inhibitors/therapeutic use
MH  - *Angiogenesis Inhibitors/therapeutic use
MH  - *Antibodies, Monoclonal/therapeutic use
MH  - Allografts
OTO - NOTNLM
OT  - Angiokinase inhibitor
OT  - Immune checkpoint inhibitor
OT  - Malignant pleural mesothelioma
OT  - Nintedanib
OT  - Tumor-associated macrophage
OT  - anti-PD-1 Ab
COIS- Declaration of Competing Interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2023/05/06 09:42
MHDA- 2023/05/19 06:41
CRDT- 2023/05/05 18:05
PHST- 2023/03/16 00:00 [received]
PHST- 2023/04/21 00:00 [revised]
PHST- 2023/04/24 00:00 [accepted]
PHST- 2023/05/19 06:41 [medline]
PHST- 2023/05/06 09:42 [pubmed]
PHST- 2023/05/05 18:05 [entrez]
AID - S0169-5002(23)00757-2 [pii]
AID - 10.1016/j.lungcan.2023.107219 [doi]
PST - ppublish
SO  - Lung Cancer. 2023 Jun;180:107219. doi: 10.1016/j.lungcan.2023.107219. Epub 2023 
      Apr 26.