Calreticulin promotes tumor lymphocyte infiltration and enhances the antitumor effects of immunotherapy by up-regulating the endothelial expression of adhesion molecules

Hao Tien Wang, Hsin I. Lee, Jih Huong Guo, Shih Hui Chen, Zhe Kang Liao, Kai Wen Huang, Pao Ling Torng, Lih Hwa Hwang*

*此作品的通信作者

研究成果: Article同行評審

42 引文 斯高帕斯(Scopus)

摘要

Tumor-induced angiogenesis has been shown to suppress immune responses. One mechanism is to suppress leukocyte-endothelial cell interaction by down-regulating the expression of adhesion molecules, such as intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1 and E-selectin on the tumor endothelium, which enables tumor cells to escape immune surveillance. Calreticulin (CRT), a chaperone protein mainly located in the endoplasmic reticulum, has been shown to exert anti-angiogenic activity and inhibit tumor growth. Here, we demonstrate that in addition to inhibiting angiogenesis, CRT also enhances the expression of both ICAM-1 and VCAM-1 on tumor endothelial cells. This expression results in enhanced leukocyte-endothelial cell interactions and increased lymphocyte infiltration into tumors. Therefore, combining intramuscular CRT gene transfer with intratumoral cytokine gene therapies significantly improves the antitumor effects of immunotherapy by markedly increasing the levels of tumor-infiltrating lymphocytes. This combined treatment increased the levels of infiltrating lymphocytes to those achieved using four times the cytokine dosage. The combined therapy also resulted in lower levels of immunosuppressive molecules and higher levels of activated T-cells in the tumor microenvironment than immunotherapy alone. In conclusion, this study describes a new antitumor mechanism of CRT that involves the up-regulation of tumor endothelial adhesion molecules and the enhanced infiltration of tumor-specific lymphocytes. Thus, CRT treatment can make tumor cells more vulnerable to immunotherapy and improve the therapeutic efficacy of immunotherapy.

原文English
頁(從 - 到)2892-2902
頁數11
期刊International Journal of Cancer
130
發行號12
DOIs
出版狀態Published - 15 6月 2012

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