PMID- 34758826
OWN - NLM
STAT- MEDLINE
DCOM- 20211126
LR  - 20211126
IS  - 1423-0127 (Electronic)
IS  - 1021-7770 (Print)
IS  - 1021-7770 (Linking)
VI  - 28
IP  - 1
DP  - 2021 Nov 10
TI  - Proteasome inhibitors restore the STAT1 pathway and enhance the expression of MHC 
      class I on human colon cancer cells.
PG  - 75
LID - 10.1186/s12929-021-00769-9 [doi]
LID - 75
AB  - BACKGROUND: A new strategy, particularly a novel combination, for immunotherapy 
      in microsatellite stable metastatic colorectal cancer (mCRC) treatment needs to 
      be formulated. Studies on the interferon-gamma (IFN-gamma)/ Janus kinase (JAK)/ signal 
      transducer and activator of transcription (STAT)1 pathway provide new directions 
      in this regard. METHODS: Our study applies three colon cancer cell lines, 
      including microsatellite stable (MSS) cell lines, which are SW480 and SW620, and 
      microsatellite instability-high (MSI-H) cell line, which is DLD-1. We compared 
      the expressions of immune surface markers on colon cancer cells in response to 
      IFN-gamma. We elucidated these mechanisms, which involved the upregulation of immune 
      surface markers. Furthermore, we examined real-world clinical samples using the 
      PerkinElmer Opal multiplex system and NanoString analysis. RESULTS: We 
      established that the baseline expression of major histocompatibility complex 
      (MHC) class I alleles and programmed death-ligand 1 (PD-L1) were generally low in 
      cell line models. The immune surface markers were significantly increased after 
      IFN-gamma stimulation on SW480 but were notably unresponsive on the SW620 cell line. 
      We discovered that STAT1 and phosphorylated STAT1 (pSTAT1) were downregulated in 
      the SW620 cell line. We verified that the STAT1/pSTAT1 could be restored through 
      the application of proteasome inhibitors, especially bortezomib. The expression 
      of MHC class I as downstream signals of STAT1 was also up-regulated by proteasome 
      inhibitors. The similar results were reproduced in DLD-1 cell line, which was 
      also initially unresponsive to IFN-gamma. In real-world samples of patients with 
      mCRC, we found that higher STAT1 expression in tumor cells was strongly 
      indicative of a highly immunogenic microenvironment, with significantly higher 
      expression levels of MHC class I and PD-L1, not only on tumor cells but also on 
      non-tumor cells. Furthermore, tumor infiltrating lymphocytes (TILs) were 
      increased in the positive-STAT1 group. Through NanoString analysis, we confirmed 
      that the mRNA expressions of IFN-gamma, human leukocyte antigen (HLA)-A, HLA-E, and 
      HLA-G were also significantly higher in the positive-STAT1 group than those in 
      the negative-STAT1 group. CONCLUSION: Our study provides a novel rationale for 
      the addition of bortezomib, a proteasome inhibitor, into new immunotherapy 
      combinations.
CI  - (c) 2021. The Author(s).
FAU - Liang, Yi-Hsin
AU  - Liang YH
AD  - Graduate Institutes of Oncology, National Taiwan University College of Medicine, 
      No 7, Chung-Shan South Rd, Taipei, 10002, Taiwan, R.O.C.
AD  - Graduate Institutes of Centers of Genomic and Precision Medicine, National Taiwan 
      University College of Medicine, Taipei, Taiwan, R.O.C.
AD  - Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan, 
      R.O.C.
AD  - National Taiwan University Cancer Center, Taipei, Taiwan, R.O.C.
FAU - Chen, Kuo-Hsing
AU  - Chen KH
AD  - Graduate Institutes of Oncology, National Taiwan University College of Medicine, 
      No 7, Chung-Shan South Rd, Taipei, 10002, Taiwan, R.O.C.
AD  - Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan, 
      R.O.C.
AD  - National Taiwan University Cancer Center, Taipei, Taiwan, R.O.C.
FAU - Tsai, Jia-Huei
AU  - Tsai JH
AD  - Departments of Pathology, National Taiwan University Hospital, Taipei, Taiwan, 
      R.O.C.
FAU - Cheng, Yung-Ming
AU  - Cheng YM
AD  - Departments of Pathology, National Taiwan University Hospital, Taipei, Taiwan, 
      R.O.C.
FAU - Lee, Chang-Cheng
AU  - Lee CC
AD  - Graduate Institutes of Oncology, National Taiwan University College of Medicine, 
      No 7, Chung-Shan South Rd, Taipei, 10002, Taiwan, R.O.C.
AD  - Graduate Institutes of Clinical Medicine, National Taiwan University College of 
      Medicine, Taipei, Taiwan, R.O.C.
FAU - Kao, Chiu-Hwa
AU  - Kao CH
AD  - Graduate Institutes of Oncology, National Taiwan University College of Medicine, 
      No 7, Chung-Shan South Rd, Taipei, 10002, Taiwan, R.O.C.
AD  - Graduate Institutes of Clinical Medicine, National Taiwan University College of 
      Medicine, Taipei, Taiwan, R.O.C.
FAU - Chan, Kuang-Yu
AU  - Chan KY
AD  - Graduate Institutes of Oncology, National Taiwan University College of Medicine, 
      No 7, Chung-Shan South Rd, Taipei, 10002, Taiwan, R.O.C.
FAU - Chen, Yeh-Ting
AU  - Chen YT
AD  - Graduate Institutes of Centers of Genomic and Precision Medicine, National Taiwan 
      University College of Medicine, Taipei, Taiwan, R.O.C.
FAU - Hsu, Wen-Ling
AU  - Hsu WL
AD  - Graduate Institutes of Centers of Genomic and Precision Medicine, National Taiwan 
      University College of Medicine, Taipei, Taiwan, R.O.C.
FAU - Yeh, Kun-Huei
AU  - Yeh KH
AUID- ORCID: 0000-0002-7306-174X
AD  - Graduate Institutes of Oncology, National Taiwan University College of Medicine, 
      No 7, Chung-Shan South Rd, Taipei, 10002, Taiwan, R.O.C.. khyeh@ntu.edu.tw.
AD  - Graduate Institutes of Clinical Medicine, National Taiwan University College of 
      Medicine, Taipei, Taiwan, R.O.C.. khyeh@ntu.edu.tw.
AD  - Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan, 
      R.O.C.. khyeh@ntu.edu.tw.
AD  - National Taiwan University Cancer Center, Taipei, Taiwan, R.O.C.. 
      khyeh@ntu.edu.tw.
LA  - eng
GR  - MOST-106-2314-B-002-222-MY3/Ministry of Science and Technology, Taiwan/
GR  - MOST-109-2634-F-002-043/Ministry of Science and Technology, Taiwan/
PT  - Journal Article
DEP - 20211110
PL  - England
TA  - J Biomed Sci
JT  - Journal of biomedical science
JID - 9421567
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Proteasome Inhibitors)
RN  - 0 (STAT1 Transcription Factor)
RN  - 0 (STAT1 protein, human)
SB  - IM
MH  - Cell Line, Tumor
MH  - Colonic Neoplasms/*physiopathology
MH  - Gene Expression/*drug effects
MH  - Genes, MHC Class I/*drug effects
MH  - Histocompatibility Antigens Class I/*genetics
MH  - Humans
MH  - Proteasome Inhibitors/*pharmacology
MH  - STAT1 Transcription Factor/*genetics/metabolism
MH  - Signal Transduction/*drug effects
PMC - PMC8579664
OTO - NOTNLM
OT  - Colorectal cancer
OT  - Interferon-gamma (IFN-gamma)
OT  - Major histocompatibility complex (MHC) class I
OT  - Proteasome inhibitors
OT  - STAT1
OT  - Tumor infiltrating lymphocytes (TILs)
COIS- The authors declare no competing interests in relation to this study.
EDAT- 2021/11/12 06:00
MHDA- 2021/11/27 06:00
PMCR- 2021/11/10
CRDT- 2021/11/11 05:43
PHST- 2021/06/07 00:00 [received]
PHST- 2021/10/20 00:00 [accepted]
PHST- 2021/11/11 05:43 [entrez]
PHST- 2021/11/12 06:00 [pubmed]
PHST- 2021/11/27 06:00 [medline]
PHST- 2021/11/10 00:00 [pmc-release]
AID - 10.1186/s12929-021-00769-9 [pii]
AID - 769 [pii]
AID - 10.1186/s12929-021-00769-9 [doi]
PST - epublish
SO  - J Biomed Sci. 2021 Nov 10;28(1):75. doi: 10.1186/s12929-021-00769-9.