Synergizing sunitinib and radiofrequency ablation to treat hepatocellular cancer by triggering the antitumor immune response.
Synergizing sunitinib and radiofrequency ablation to treat hepatocellular cancer by triggering the antitumor immune response.
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DOI：
10.1136/jitc-2020-001038
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发表时间：
2020-10
影响因子：
10.9
通讯作者：
Li G
中科院分区：
文献类型：
--
作者：
Qi X;Yang M;Ma L;Sauer M;Avella D;Kaifi JT;Bryan J;Cheng K;Staveley-O'Carroll KF;Kimchi ET;Li G
Minimally invasive radiofrequency ablation (RFA) is used as a first-line treatment option for hepatocellular cancer (HCC) with the weaknesses of incomplete ablation, tumor recurrence, and inferior outcomes. To overcome this limitation, we proposed to develop sunitinib-RFA integrated therapy with a potential of activating anti-HCC immune response. Using our unique murine model, we developed a novel RFA platform with a modified human cardiac RF generator. Therapeutic efficacy of sunitinib–RFA combined treatment in HCC was tested in this platform. Tumor progression was monitored by MRI; tumor necrosis and apoptosis were detected by H&E and terminal deoxynucleotidyl transferase dUTP nick end labeling; immune reaction was defined by flow cytometry; and signaling molecules were examined with real-time PCR (qPCR), western blot, and immunohistochemical staining. A significantly reduced tumor growth and extended lift span were observed in the mice receiving combined treatment with RFA and sunitinib. This combined treatment significantly increased the frequency of CD8+ T cell, memory CD8+ T cell, and dendritic cells (DCs); decreased the frequency of regulatory T cells; and activated tumor-specific antigen (TSA) immune response in tumor microenvironment. We found that RFA caused PD-1 upregulation in tumor-infiltrated T cells by boosting hepatocyte growth factor (HGF) expression, which was suppressed by sunitinib treatment. We have also demonstrated that sunitinib suppressed VEGF’s effect in enhancing PD-L1 expression in DCs and attenuated heat-sink effect. The results indicate that RFA induced tumor destruction and release of in situ TSAs which can activate a tumoricidal immune response in sunitinib-treated mice, significantly improving anti-HCC therapeutic efficacy. Sunitinib enables RFA-released in situ TSA to ignite an effective anti-tumor immune response by suppressing HGF and VEGF signaling pathways. Sunitinib–RFA as a synergistic therapeutic approach significantly suppresses HCC growth.
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影响因子：
11.2
作者：
Ozao-Choy J;Ma G;Kao J;Wang GX;Meseck M;Sung M;Schwartz M;Divino CM;Pan PY;Chen SH
通讯作者：
Chen SH
影响因子：
29.4
作者：
Li G;Liu D;Kimchi ET;Kaifi JT;Qi X;Manjunath Y;Liu X;Deering T;Avella DM;Fox T;Rockey DC;Schell TD;Kester M;Staveley-O'Carroll KF
通讯作者：
Staveley-O'Carroll KF
DOI：
10.1016/j.bbrc.2005.06.065
发表时间：
2005-08-19
影响因子：
3.1
作者：
Laxmanan, S;Robertson, SW;Mukhopadhyay, D
通讯作者：
Mukhopadhyay, D
影响因子：
13.5
作者：
Avella, Diego M.;Li, Guangfu;Schell, Todd D.;Liu, Dai;Zhang, Samuel Shao-Min;Lou, Xi;Berg, Arthur;Kimchi, Eric T.;Tagaram, Hephzibah Rani S.;Yang, Qing;Shereef, Serene;Garcia, Luis S.;Kester, Mark;Isom, Harriet C.;Rountree, C. Bart;Staveley-O'Carroll, Kevin F.
通讯作者：
Staveley-O'Carroll, Kevin F.
影响因子：
25.7
作者：
Li G;Liu D;Cooper TK;Kimchi ET;Qi X;Avella DM;Li N;Yang QX;Kester M;Rountree CB;Kaifi JT;Cole DJ;Rockey DC;Schell TD;Staveley-O'Carroll KF
通讯作者：
Staveley-O'Carroll KF