PMID- 37279067
OWN - NLM
STAT- MEDLINE
DCOM- 20230803
LR  - 20230804
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 133
IP  - 15
DP  - 2023 Aug 1
TI  - SCCA1/SERPINB3 suppresses antitumor immunity and blunts therapy-induced T cell 
      responses via STAT-dependent chemokine production.
LID - 10.1172/JCI163841 [doi]
LID - e163841
AB  - Patients with cancer who have high serum levels of squamous cell carcinoma 
      antigen 1 (SCCA1, now referred to as SERPINB3) commonly experience treatment 
      resistance and have a poor prognosis. Despite being a clinical biomarker, the 
      modulation of SERPINB3 in tumor immunity is poorly understood. We found positive 
      correlations of SERPINB3 with CXCL1, CXCL8 (CXCL8/9), S100A8, and S100A9 
      (S100A8/A9) myeloid cell infiltration through RNA-Seq analysis of human primary 
      cervical tumors. Induction of SERPINB3 resulted in increased CXCL1/8 and 
      S100A8/A9 expression, which promoted monocyte and myeloid-derived suppressor cell 
      (MDSC) migration in vitro. In mouse models, Serpinb3a tumors showed increased 
      MDSC and tumor-associated macrophage (TAM) infiltration, contributing to T cell 
      inhibition, and this was further augmented upon radiation. Intratumoral knockdown 
      (KD) of Serpinb3a resulted in tumor growth inhibition and reduced CXCL1 and 
      S100A8/A expression and MDSC and M2 macrophage infiltration. These changes led to 
      enhanced cytotoxic T cell function and sensitized tumors to radiotherapy (RT). We 
      further revealed that SERPINB3 promoted STAT-dependent expression of chemokines, 
      whereby inhibition of STAT activation by ruxolitinib or siRNA abrogated CXCL1/8 
      and S100A8/ A9 expression in SERPINB3 cells. Patients with elevated pretreatment 
      SCCA levels and high phosphorylated STAT3 (p-STAT3) had increased intratumoral 
      CD11b+ myeloid cells compared with patients with low SCCA levels and p-STAT3, who 
      had improved overall survival after RT. These findings provide a preclinical 
      rationale for targeting SERPINB3 in tumors to counteract immunosuppression and 
      improve the response to RT.
FAU - Chen, Liyun
AU  - Chen L
AD  - Department of Radiation Oncology.
FAU - Shi, Victoria
AU  - Shi V
AD  - Department of Radiation Oncology.
FAU - Wang, Songyan
AU  - Wang S
AD  - Department of Radiation Oncology.
FAU - Sun, Lulu
AU  - Sun L
AD  - Department of Pathology and Immunology.
FAU - Freeman, Rebecca
AU  - Freeman R
AD  - Department of Radiation Oncology.
FAU - Yang, Jasmine
AU  - Yang J
AD  - Department of Radiation Oncology.
FAU - Inkman, Matthew J
AU  - Inkman MJ
AD  - Department of Radiation Oncology.
FAU - Ghosh, Subhajit
AU  - Ghosh S
AD  - Department of Radiation Oncology.
FAU - Ruiz, Fiona
AU  - Ruiz F
AD  - Department of Radiation Oncology.
FAU - Jayachandran, Kay
AU  - Jayachandran K
AD  - Department of Radiation Oncology.
FAU - Huang, Yi
AU  - Huang Y
AD  - Department of Radiation Oncology.
FAU - Luo, Jingqin
AU  - Luo J
AD  - Department of Surgery, Division of Public Health Sciences, and.
FAU - Zhang, Jin
AU  - Zhang J
AD  - Department of Radiation Oncology.
AD  - Alvin J Siteman Cancer Center, Washington University School of Medicine, St 
      Louis, Missouri, USA.
FAU - Cosper, Pippa
AU  - Cosper P
AD  - Department of Radiation Oncology.
AD  - Department of Human Oncology, University of Wisconsin School of Medicine and 
      Public Health, Madison, Wisconsin, USA.
FAU - Luke, Clifford J
AU  - Luke CJ
AD  - Alvin J Siteman Cancer Center, Washington University School of Medicine, St 
      Louis, Missouri, USA.
AD  - Department of Pediatrics, Washington University School of Medicine, St Louis, 
      Missouri, USA.
FAU - Spina, Catherine S
AU  - Spina CS
AD  - Department of Radiation Oncology, Columbia University Irving Medical Center, New 
      York, New York, USA.
FAU - Grigsby, Perry W
AU  - Grigsby PW
AD  - Alvin J Siteman Cancer Center, Washington University School of Medicine, St 
      Louis, Missouri, USA.
AD  - Department of Radiology, Washington University School of Medicine, St Louis, 
      Missouri, USA.
FAU - Schwarz, Julie K
AU  - Schwarz JK
AD  - Department of Radiation Oncology.
AD  - Alvin J Siteman Cancer Center, Washington University School of Medicine, St 
      Louis, Missouri, USA.
FAU - Markovina, Stephanie
AU  - Markovina S
AD  - Department of Radiation Oncology.
AD  - Alvin J Siteman Cancer Center, Washington University School of Medicine, St 
      Louis, Missouri, USA.
LA  - eng
GR  - K08 CA237822/CA/NCI NIH HHS/United States
GR  - K22 CA237839/CA/NCI NIH HHS/United States
GR  - P30 CA091842/CA/NCI NIH HHS/United States
GR  - R01 CA181745/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20230801
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (squamous cell carcinoma-related antigen)
RN  - 0 (Calgranulin A)
RN  - 0 (Calgranulin B)
RN  - 0 (Serpins)
RN  - 0 (Chemokines)
SB  - IM
MH  - Mice
MH  - Animals
MH  - Humans
MH  - *Calgranulin A/genetics
MH  - Calgranulin B/genetics
MH  - *Serpins/genetics
MH  - Chemokines/metabolism
PMC - PMC10378164
OTO - NOTNLM
OT  - Cervical cancer
OT  - Oncology
OT  - Radiation therapy
COIS- Conflict of interest: The authors have declared that no conflict of interest 
      exists
EDAT- 2023/06/06 13:09
MHDA- 2023/08/03 06:43
PMCR- 2023/08/01
CRDT- 2023/06/06 12:03
PHST- 2022/08/12 00:00 [received]
PHST- 2023/06/02 00:00 [accepted]
PHST- 2023/08/03 06:43 [medline]
PHST- 2023/06/06 13:09 [pubmed]
PHST- 2023/06/06 12:03 [entrez]
PHST- 2023/08/01 00:00 [pmc-release]
AID - 163841 [pii]
AID - 10.1172/JCI163841 [doi]
PST - epublish
SO  - J Clin Invest. 2023 Aug 1;133(15):e163841. doi: 10.1172/JCI163841.