Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Jan;38(4):533-548.
doi: 10.1038/s41388-018-0449-z. Epub 2018 Aug 29.

STAT3 inhibition induces Bax-dependent apoptosis in liver tumor myeloid-derived suppressor cells

Prajna Guha  1 , Jillian Gardell  1 , Josephine Darpolor  1 , Marissa Cunetta  1 , Matthew Lima  1 , George Miller  2 , N Joseph Espat  1   3 , Richard P Junghans  1 , Steven C Katz  4   5
Affiliations

STAT3 inhibition induces Bax-dependent apoptosis in liver tumor myeloid-derived suppressor cells

Prajna Guha et al. Oncogene. 2019 Jan.

Abstract

Immunosuppressive myeloid-derived suppressor cells (MDSC) subvert antitumor immunity and limit the efficacy of chimeric antigen receptor T cells (CAR-T). Previously, we reported that the GM-CSF/JAK2/STAT3 axis drives liver-associated MDSC (L-MDSC) proliferation and blockade of this axis rescued antitumor immunity. We extended these findings in our murine liver metastasis (LM) model, by treating tumor-bearing mice with STAT3 inhibitors (STATTIC or BBI608) to further our understanding of how STAT3 drives L-MDSC suppressive function. STAT3 inhibition caused significant reduction of tumor burden as well as L-MDSC frequencies due to decrease in pSTAT3 levels. L-MDSC isolated from STATTIC or BBI608-treated mice had significantly reduced suppressive function. STAT3 inhibition of L-MDSC was associated with enhanced antitumor activity of CAR-T. Further investigation demonstrated activation of apoptotic signaling pathways in L-MDSC following STAT3 inhibition as evidenced by an upregulation of the pro-apoptotic proteins Bax, cleaved caspase-3, and downregulation of the anti-apoptotic protein Bcl-2. Accordingly, there was also a decrease of pro-survival markers, pErk and pAkt, and an increase in pro-death marker, Fas, with activation of downstream JNK and p38 MAPK. These findings represent a previously unrecognized link between STAT3 inhibition and Fas-induced apoptosis of MDSCs. Our findings suggest that inhibiting STAT3 has potential clinical application for enhancing the efficacy of CAR-T cells in LM through modulation of L-MDSC.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Guha P, Reha J, Katz SC. Immunosuppression in liver tumors: opening the portal to effective immunotherapy. Cancer Gene Ther. 2017;24:114–20. - DOI
    1. Katz SC, Pillarisetty VG, Bleier JI, Kingham TP, Chaudhry UI, Shah AB, et al. Conventional liver CD4 T cells are functionally distinct and suppressed by environmental factors. Hepatology. 2005;42:293–300. - DOI
    1. Katz SC, Bamboat ZM, Maker AV, Shia J, Pillarisetty VG, Yopp AC, et al. Regulatory T cell infiltration predicts outcome following resection of colorectal cancer liver metastases. Ann Surg Oncol. 2013;20:946–55. - DOI
    1. Katz SC, Pillarisetty V, Bamboat ZM, Shia J, Hedvat C, Gonen M, et al. T cell infiltrate predicts long-term survival following resection of colorectal cancer liver metastases. Ann Surg Oncol. 2009;16:2524–30. - DOI
    1. Turcotte S, Katz SC, Shia J, Jarnagin WR, Kingham TP, Allen PJ, et al. Tumor MHC class I expression improves the prognostic value of T-cell density in resected colorectal liver metastases. Cancer Immunol Res. 2014;2:530–7. - DOI

Publication types

MeSH terms

LinkOut - more resources

  NODES
innovation 1
INTERN 1
twitter 2