title: Rapamycin Promotes Mouse 4T1 Tumor Metastasis that Can Be Reversed by a Dendritic Cell-Based Vaccine.
abstract: Suppression of tumor metastasis is a key strategy for successful cancer interventions. Previous studies indicated that rapamycin (sirolimus) may promote tumor regression activity or enhance immune response against tumor targets. However, rapamycin also exhibits immunosuppressant effects and is hence used clinically as an organ transplantation drug. We hypothesized that the immunosuppressive activities of rapamycin might also negatively mediate host immunity, resulting in promotion of tumor metastasis. In this study, the effects of rapamycin and phytochemical shikonin were investigated in vitro and in vivo in a 4T1 mouse mammary tumor model through quantitative assessment of immunogenic cell death (ICD), autophagy, tumor growth and metastasis. Tumor-bearing mice were immunized with test vaccines to monitor their effect on tumor metastasis. We found that intraperitoneal (ip) administration of rapamycin after a tumor-resection surgery drastically increased the metastatic activity of 4T1 tumors. Possible correlation of this finding to human cancers was suggested by epidemiological analysis of data from Taiwan's National Health Insurance Research Database (NHIRD). Since our previous studies showed that modified tumor cell lysate (TCL)-pulsed, dendritic cell (DC)-based cancer vaccines can effectively suppress metastasis in mouse tumor models, we assessed whether such vaccines may help offset this rapamycin-promoted metastasis. We observed that shikonin efficiently induced ICD of 4T1 cells in culture, and DC vaccines pulsed with shikonin-treated TCL (SK-TCL-DC) significantly suppressed rapamycin-enhanced metastasis and Treg cell expansion in test mice. In conclusion, rapamycin treatment in mice (and perhaps in humans) promotes metastasis and the effect may be offset by treatment with a DC-based cancer vaccine.
authors.affiliation: Graduate Institute of Injury Prevention and Control, Taipei Medical University, Taipei, Taiwan, ROC; Department of Neurosurgery, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan, ROC; Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan, ROC; Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, Taiwan, ROC; Taiwan International Graduate Program (TIGP), Molecular and Biological Agricultural Sciences Program, Academia Sinica, Taipei, Taiwan, ROC.
authors.forename: Tien-Jen
authors.initials: TJ
authors.lastname: Lin
authors.affiliation: Biostatistics Center, China Medical University, Taichung, Taiwan, ROC; Institute of Environmental Health, Department of Public Health, School of Public Health, China Medical University, Taichung, Taiwan, ROC.
authors.forename: Wen-Miin
authors.initials: WM
authors.lastname: Liang
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan, ROC; Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, Taiwan, ROC; Taiwan International Graduate Program (TIGP), Molecular and Biological Agricultural Sciences Program, Academia Sinica, Taipei, Taiwan, ROC.
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Hsiao
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan, ROC; Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, Taiwan, ROC; Taiwan International Graduate Program (TIGP), Molecular and Biological Agricultural Sciences Program, Academia Sinica, Taipei, Taiwan, ROC.
authors.forename: Pradeep
authors.initials: P
authors.lastname: M S
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan, ROC.
authors.forename: Wen-Chi
authors.initials: WC
authors.lastname: Wei
authors.affiliation: Department of Neurosurgery, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan, ROC; Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan, ROC.
authors.forename: Hsin-Ting
authors.initials: HT
authors.lastname: Lin
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan, ROC.
authors.forename: Shu-Yi
authors.initials: SY
authors.lastname: Yin
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan, ROC; Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, Taiwan, ROC; Taiwan International Graduate Program (TIGP), Molecular and Biological Agricultural Sciences Program, Academia Sinica, Taipei, Taiwan, ROC.
authors.forename: Ning-Sun
authors.initials: NS
authors.lastname: Yang
mesh_terms: D000328:Adult; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology*; D005260:Female; D006801:Humans; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009285:Naphthoquinones / Q000009:adverse effects; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000139:chemically induced / Q000453:epidemiology; D020123:Sirolimus / Q000009:adverse effects*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology; D055815:Young Adult
chemical_list: D019496:Cancer Vaccines; D009285:Naphthoquinones; C016101:shikonin; D020123:Sirolimus