STAT3 inhibitory stattic enhances immunogenic cell death induced by chemotherapy in cancer cells
Induction of immunogenic cell death (ICD) is considered a promising strategy for cancer immunotherapy. Stattic is an inhibitor of STAT3, which is found constitutively active in many cancers and plays a major role in cancer progression.
In the present study, we proposed to evaluate whether stattic can enhance the effects of chemotherapy in the induction of ICD in cancer cells harboring hyperactive STAT3.
The growth inhibitory effects of stattic and chemo agents including doxorubicin (DOX) and oxaliplatin (OXP) were evaluated using MTT assay in B16F10 and CT26 cell lines. Flow cytometry was applied to study cell apoptosis and calreticulin (CRT) surface exposure. The levels of high mobility group box 1 (HGMB1), heat shock protein70 (HSP70) and interleukin-12 (IL-12) were measured using ELISA.
Treatment of B16F10 and CT26 cells with stattic in combination with DOX resulted in synergistic antitumor effects with combination index being 0.82 and 0.87, respectively. Interestingly, we found a higher level of ICD markers including CRT expression as well as HMGB1 and HSP70 secretion in the cells received combination therapy of stattic and DOX as compared with monotherapies. Moreover, exposure of dendritic cells (DCs) to conditioned media (CM) from cancer cells treated with stattic and/or DOX resulted in secretion of IL-12, which is an indicator of DCs maturation and induction of Th1 response. OXP and stattic monotherapy induced ICD in CT26 cells and stimulated IL-12 secretion by DCs; however, we did not observe a significant increase in the level of ICD in CT26 cells and IL-12 secretion by DCs when CT26 cells were treated with stattic and OXP combination as compared with monotherapy groups.
These findings indicate that STAT3 inhibitory stattic can increase ICD induced by DOX.
KeywordsImmunotherapy Chemotherapy Combination therapy STAT3 Melanoma Colon cancer
This study is part of a dissertation (No.128) by S.Jafari, submitted for Ph.D degree and supported financially by Biotechnology Research Center, Tabriz University of Medical Sciences.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 5.Radogna F, Diederich M. Stress-induced cellular responses in immunogenic cell death: implications for cancer immunotherapy. Biochem Pharmacol. 2018.Google Scholar
- 23.Yang H, Yamazaki T, Pietrocola F, Zhou H, Zitvogel L, Ma Y et al. STAT3 inhibition enhances the therapeutic efficacy of immunogenic chemotherapy by stimulating type 1 interferon production by cancer cells. Cancer Res. 2015:canres. 1122.2015.Google Scholar
- 25.Lee DS, Grandis JR, Johnson DE. STAT3 as a Major Contributor to Chemoresistance. Targeting Cell Survival Pathways to Enhance Response to Chemotherapy. Elsevier; 2019. p. 145–67.Google Scholar
- 37.Garg AD, Nowis D, Golab J, Vandenabeele P, Krysko DV, Agostinis P. Immunogenic cell death, DAMPs and anticancer therapeutics: an emerging amalgamation. BBA-Rev Cancer. 2010;1805(1):53–71.Google Scholar
- 38.Mattarollo SR, Loi S, Duret H, Ma Y, Zitvogel L, Smyth MJ. Pivotal role of innate and adaptive immunity in anthracycline chemotherapy of established tumors. Cancer Res. 2011:canres. 0753.2011.Google Scholar
- 41.Diederich M. Natural compound inducers of immunogenic cell death. Arch Pharm Res. 2019:1–17.Google Scholar
- 42.Zhou J, Wang G, Chen Y, Wang H, Hua Y, Cai Z. Immunogenic cell death in cancer therapy: present and emerging inducers. J Cell Mol Med. 2019.Google Scholar