TY - JOUR
T1 - Radiofrequency ablation in combination with an mTOR inhibitor restrains pancreatic cancer growth induced by intrinsic HSP70
AU - Gao, Shanshan
AU - Pu, Ning
AU - Yin, Hanlin
AU - Li, Junhao
AU - Chen, Qiangda
AU - Yang, Minjie
AU - Lou, Wenhui
AU - Chen, Yi
AU - Zhou, Guofeng
AU - Li, Changyu
AU - Li, Guoping
AU - Yan, Zhiping
AU - Liu, Lingxiao
AU - Yu, Jun
AU - Wang, Xiaolin
N1 - Funding Information:
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was funded by the Project of Shanghai Municipal Health Commission (no. 201940409).
Funding Information:
The authors thank the China Scholarship Council for supporting Dr Gao as a visiting PhD candidate at Washington University School of Medicine and Johns Hopkins University School of Medicine. They would also like to thank Editage (www.editage.com) for English language editing. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was funded by the Project of Shanghai Municipal Health Commission (no. 201940409).
Funding Information:
The authors thank the China Scholarship Council for supporting Dr Gao as a visiting PhD candidate at Washington University School of Medicine and Johns Hopkins University School of Medicine. They would also like to thank Editage ( www.editage.com ) for English language editing.
Publisher Copyright:
© The Author(s), 2020.
PY - 2020
Y1 - 2020
N2 - Background: Radiofrequency ablation (RFA) is widely used in palliative therapy of malignant cancers. Several studies have shown its applicability and safety for locally advanced pancreatic cancer (LAPC). The objective of this study was to modify the current regimen to improve its therapeutic effect. Methods: Immune cell subtypes and related cytokines were quantified to uncover the immune pattern changes post-RFA treatment. Then, high-throughput proteome analysis was performed to identify differentially expressed proteins associated with RFA, which were further validated in in vitro and in vivo experiments. Finally, a combined therapy was tested in a murine model to observe its therapeutic effect. Results: In preclinical murine models of RFA treatment, no significant therapeutic benefit was observed following RFA treatment. However, the proportion of tumor-infiltrating CD8+ T cells was significantly increased, whereas that of regulatory T cells (Tregs) was decreased post-RFA treatment, which indicated a beneficial anti-tumor environment. To identify the mechanism, high-throughput mass spectrum was obtained that identified heat shock protein 70 (HSP70) as the top differentially expressed protein. HSP70 expression in residual cancer cells was significantly increased post-RFA treatment, which notably promoted pancreatic cancer growth. Elevated HSP70 promoted cell proliferation by activating AKT–mTOR signaling. Finally, RFA treatment combined with an mTOR inhibitor exerted a synergetic repressive effect on tumor growth in the preclinical murine cancer model. Conclusions: RFA treatment in combination with mTOR signaling blockade can not only promote tumor immune response, but also restrain residual cancer cell proliferation. Such a combination may be a promising and effective therapeutic strategy for LAPC patients.
AB - Background: Radiofrequency ablation (RFA) is widely used in palliative therapy of malignant cancers. Several studies have shown its applicability and safety for locally advanced pancreatic cancer (LAPC). The objective of this study was to modify the current regimen to improve its therapeutic effect. Methods: Immune cell subtypes and related cytokines were quantified to uncover the immune pattern changes post-RFA treatment. Then, high-throughput proteome analysis was performed to identify differentially expressed proteins associated with RFA, which were further validated in in vitro and in vivo experiments. Finally, a combined therapy was tested in a murine model to observe its therapeutic effect. Results: In preclinical murine models of RFA treatment, no significant therapeutic benefit was observed following RFA treatment. However, the proportion of tumor-infiltrating CD8+ T cells was significantly increased, whereas that of regulatory T cells (Tregs) was decreased post-RFA treatment, which indicated a beneficial anti-tumor environment. To identify the mechanism, high-throughput mass spectrum was obtained that identified heat shock protein 70 (HSP70) as the top differentially expressed protein. HSP70 expression in residual cancer cells was significantly increased post-RFA treatment, which notably promoted pancreatic cancer growth. Elevated HSP70 promoted cell proliferation by activating AKT–mTOR signaling. Finally, RFA treatment combined with an mTOR inhibitor exerted a synergetic repressive effect on tumor growth in the preclinical murine cancer model. Conclusions: RFA treatment in combination with mTOR signaling blockade can not only promote tumor immune response, but also restrain residual cancer cell proliferation. Such a combination may be a promising and effective therapeutic strategy for LAPC patients.
KW - heat shock protein 70
KW - mammalian target of rapamycin
KW - microenvironment
KW - pancreatic ductal adenocarcinoma
KW - radiofrequency ablation
UR - http://www.scopus.com/inward/record.url?scp=85090767026&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85090767026&partnerID=8YFLogxK
U2 - 10.1177/1758835920953728
DO - 10.1177/1758835920953728
M3 - Article
C2 - 32973929
AN - SCOPUS:85090767026
SN - 1758-8340
VL - 12
JO - Therapeutic Advances in Medical Oncology
JF - Therapeutic Advances in Medical Oncology
ER -