title: Calreticulin promotes tumor lymphocyte infiltration and enhances the antitumor effects of immunotherapy by up-regulating the endothelial expression of adhesion molecules.
abstract: 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.
authors.affiliation: Graduate Institute of Microbiology, National Taiwan University College of Medicine, Taipei 100, Taiwan.
authors.forename: Hao-Tien
authors.initials: HT
authors.lastname: Wang
authors.forename: Hsin-I
authors.initials: HI
authors.lastname: Lee
authors.forename: Jih-Huong
authors.initials: JH
authors.lastname: Guo
authors.forename: Shih-Hui
authors.initials: SH
authors.lastname: Chen
authors.forename: Zhe-Kang
authors.initials: ZK
authors.lastname: Liao
authors.forename: Kai-Wen
authors.initials: KW
authors.lastname: Huang
authors.forename: Pao-Ling
authors.initials: PL
authors.lastname: Torng
authors.forename: Lih-Hwa
authors.initials: LH
authors.lastname: Hwang
mesh_terms: D000818:Animals; D037282:Calreticulin / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006224:Cricetinae; D019040:E-Selectin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000276:immunology; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism; D018014:Gene Transfer Techniques; D007167:Immunotherapy; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D007962:Leukocytes / Q000276:immunology; D008114:Liver Neoplasms, Experimental / Q000276:immunology* / Q000628:therapy*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic; D051381:Rats; D017208:Rats, Wistar; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019139:Tumor Escape; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D037282:Calreticulin; D019040:E-Selectin; D016328:NF-kappa B; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1