PMID- 37209991
OWN - NLM
STAT- MEDLINE
DCOM- 20230612
LR  - 20240119
IS  - 1090-2422 (Electronic)
IS  - 0014-4827 (Linking)
VI  - 429
IP  - 1
DP  - 2023 Aug 1
TI  - Regorafenib induces damage-associated molecular patterns, cancer cell death and 
      immune modulatory effects in a murine triple negative breast cancer model.
PG  - 113652
LID - S0014-4827(23)00199-4 [pii]
LID - 10.1016/j.yexcr.2023.113652 [doi]
AB  - Damage associated molecular patterns (DAMPs), including calreticulin (CRT) 
      exposure, high-mobility group box 1 protein (HMGB1) elevation, and ATP release, 
      characterize immunogenic cell death (ICD) and may play a role in cancer 
      immunotherapy. Triple negative breast cancer (TNBC) is an immunogenic subtype of 
      breast cancer with higher lymphocyte infiltration. Here, we found that 
      regorafenib, a multi-target angiokinase inhibitor previously known to suppress 
      STAT3 signaling, induced DAMPs and cell death in TNBC cells. Regorafenib induced 
      the expression of HMGB1 and CRT, and the release of ATP. Regorafenib-induced 
      HMGB1 and CRT were attenuated following STAT3 overexpression. In a 4T1 syngeneic 
      murine model, regorafenib treatment increased HMGB1 and CRT expression in 
      xenografts, and effectively suppressed 4T1 tumor growth. Immunohistochemical 
      staining revealed increased CD4(+) and CD8(+) tumor-infiltrating T cells in 4T1 
      xenografts following regorafenib treatment. Regorafenib treatment or programmed 
      death-1 (PD-1) blockade using anti-PD-1 monoclonal antibody reduced lung 
      metastasis of 4T1 cells in immunocompetent mice. While regorafenib increases the 
      proportion of MHC II high expression on dendritic cells in mice with smaller 
      tumors, the combination of regorafenib and PD-1 blockade did not show a 
      synergistic effect on anti-tumor activity. These results suggest that regorafenib 
      induces ICD and suppresses tumor progression in TNBC. It should be carefully 
      evaluated when developing a combination therapy with an anti-PD-1 antibody and a 
      STAT3 inhibitor.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Tseng, Ling-Ming
AU  - Tseng LM
AD  - Division of General Surgery, Department of Surgery, Taipei Veterans General 
      Hospital, Taipei, Taiwan; Comprehensive Breast Health Center, Taipei Veterans 
      General Hospital, Taipei, Taiwan; School of Medicine, College of Medicine, 
      National Yang Ming Chiao Tung University, Taipei, Taiwan.
FAU - Lau, Ka-Yi
AU  - Lau KY
AD  - Division of Medical Oncology, Department of Oncology, Taipei Veterans General 
      Hospital, Taipei, Taiwan.
FAU - Chen, Ji-Lin
AU  - Chen JL
AD  - Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei, 
      Taiwan; Division of Medical Oncology, Department of Oncology, Taipei Veterans 
      General Hospital, Taipei, Taiwan.
FAU - Chu, Pei-Yi
AU  - Chu PY
AD  - Department of Pathology, Show Chwan Memorial Hospital, Changhua City, Taiwan; 
      School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 
      Department of Health Food, Chung Chou University of Science and Technology, 
      Changhua, Taiwan.
FAU - Huang, Tzu-Ting
AU  - Huang TT
AD  - Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei, 
      Taiwan; Division of Medical Oncology, Department of Oncology, Taipei Veterans 
      General Hospital, Taipei, Taiwan.
FAU - Lee, Chia-Han
AU  - Lee CH
AD  - Division of Medical Oncology, Department of Oncology, Taipei Veterans General 
      Hospital, Taipei, Taiwan.
FAU - Wang, Wan-Lun
AU  - Wang WL
AD  - Division of General Surgery, Department of Surgery, Taipei Veterans General 
      Hospital, Taipei, Taiwan; Comprehensive Breast Health Center, Taipei Veterans 
      General Hospital, Taipei, Taiwan.
FAU - Chang, Yuan-Ya
AU  - Chang YY
AD  - Division of Medical Oncology, Department of Oncology, Taipei Veterans General 
      Hospital, Taipei, Taiwan.
FAU - Huang, Chun-Teng
AU  - Huang CT
AD  - Division of Hematology & Oncology, Department of Medicine, Yang-Ming Branch of 
      Taipei City Hospital, Taipei, Taiwan.
FAU - Huang, Chi-Cheng
AU  - Huang CC
AD  - Division of General Surgery, Department of Surgery, Taipei Veterans General 
      Hospital, Taipei, Taiwan; Comprehensive Breast Health Center, Taipei Veterans 
      General Hospital, Taipei, Taiwan; Institute of Epidemiology and Preventive 
      Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
FAU - Chao, Ta-Chung
AU  - Chao TC
AD  - Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei, 
      Taiwan; School of Medicine, College of Medicine, National Yang Ming Chiao Tung 
      University, Taipei, Taiwan; Division of Chemotherapy, Department of Oncology, 
      Taipei Veterans General Hospital, Taipei, Taiwan.
FAU - Tsai, Yi-Fang
AU  - Tsai YF
AD  - Division of General Surgery, Department of Surgery, Taipei Veterans General 
      Hospital, Taipei, Taiwan; Comprehensive Breast Health Center, Taipei Veterans 
      General Hospital, Taipei, Taiwan; School of Medicine, College of Medicine, 
      National Yang Ming Chiao Tung University, Taipei, Taiwan.
FAU - Lai, Jiun-I
AU  - Lai JI
AD  - Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei, 
      Taiwan; Division of Medical Oncology, Department of Oncology, Taipei Veterans 
      General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, School of 
      Medicine, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
FAU - Dai, Ming-Shen
AU  - Dai MS
AD  - Hematology/Oncology, Tri-Service General Hospital, National Defense Medical 
      Centre, Taipei, Taiwan.
FAU - Liu, Chun-Yu
AU  - Liu CY
AD  - Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei, 
      Taiwan; School of Medicine, College of Medicine, National Yang Ming Chiao Tung 
      University, Taipei, Taiwan; Division of Medical Oncology, Department of Oncology, 
      Taipei Veterans General Hospital, Taipei, Taiwan; Division of Transfusion 
      Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, 
      Taiwan. Electronic address: cyliu3@vghtpe.gov.tw.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230518
PL  - United States
TA  - Exp Cell Res
JT  - Experimental cell research
JID - 0373226
RN  - 24T2A1DOYB (regorafenib)
RN  - 0 (HMGB1 Protein)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
SB  - IM
MH  - Mice
MH  - Humans
MH  - Animals
MH  - *Triple Negative Breast Neoplasms/drug therapy/metabolism
MH  - *HMGB1 Protein/pharmacology
MH  - Cell Death
MH  - Adenosine Triphosphate/pharmacology
MH  - Cell Line, Tumor
OTO - NOTNLM
OT  - Immunogenic cell death
OT  - Regorafenib
OT  - Triple negative breast cancer
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- 2023/05/21 01:05
MHDA- 2023/06/12 06:42
CRDT- 2023/05/20 19:29
PHST- 2022/10/06 00:00 [received]
PHST- 2023/05/13 00:00 [revised]
PHST- 2023/05/15 00:00 [accepted]
PHST- 2023/06/12 06:42 [medline]
PHST- 2023/05/21 01:05 [pubmed]
PHST- 2023/05/20 19:29 [entrez]
AID - S0014-4827(23)00199-4 [pii]
AID - 10.1016/j.yexcr.2023.113652 [doi]
PST - ppublish
SO  - Exp Cell Res. 2023 Aug 1;429(1):113652. doi: 10.1016/j.yexcr.2023.113652. Epub 
      2023 May 18.