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. 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
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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.

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