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Rapamycin Promotes Mouse 4T1 Tumor Metastasis that Can Be Reversed by a Dendritic Cell-Based Vaccine.

Lin TJ, Liang WM, Hsiao PW, M S P, Wei WC, Lin HT, Yin SY, Yang NS - PLoS ONE (2015)

Bottom Line: Suppression of tumor metastasis is a key strategy for successful cancer interventions.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

Hypothetical model depicting a possible interaction between in-vivo rapamycin treatment and ex-vivo DC-based immunotherapy for effective balance/maintenance of different T lymphocyte activities in suppression of mammary carcinoma metastasis.
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pone.0138335.g006: Hypothetical model depicting a possible interaction between in-vivo rapamycin treatment and ex-vivo DC-based immunotherapy for effective balance/maintenance of different T lymphocyte activities in suppression of mammary carcinoma metastasis.

Mentions: Relevant to these rapamycin-mediated Treg cell activities,[41] in our previous and present studies we showed that shikonin can effectively induce the expression of specific DAMPs, which can in turn activate caspase cascades in treated B16 and 4T1 cells.[11] In combination with DAMPs, shikonin-induced TCL can activate DCs to a full level of phenotypic and functional maturation, which in turn can promote the development of Th1 cells and the induction of cytotoxic T lymphocyte activities and their secretory expression of a specific Th1 cytokine, IFN-γ (Fig 3D). Together, these activities, and in combination with the decrease in MDSC and Treg cell activities (Fig 5), we believe, may contribute to a highly efficacious retardation of tumor growth and prolong the survival of test mice. Based on these findings, we propose a hypothetical model (Fig 6) to describe the possible immuno-cellular mechanisms by which a dendritic cell-based immunotherapeutic vaccine, when administered concomitantly with rapamycin in vivo, may provide a beneficial effect to counter balance, offset and maintain the activities of specific subsets of T lymphocytes, useful for treatment of cancer patients. Among the different phytochemicals tested in this study and our previous investigation,[11] shikonin shows the highest activity in promotion of ICD in treated tumor cells, we therefore consider that further clinical evaluation of shikonin in human immune cell-based therapy is warranted.


Rapamycin Promotes Mouse 4T1 Tumor Metastasis that Can Be Reversed by a Dendritic Cell-Based Vaccine.

Lin TJ, Liang WM, Hsiao PW, M S P, Wei WC, Lin HT, Yin SY, Yang NS - PLoS ONE (2015)

Hypothetical model depicting a possible interaction between in-vivo rapamycin treatment and ex-vivo DC-based immunotherapy for effective balance/maintenance of different T lymphocyte activities in suppression of mammary carcinoma metastasis.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4591294&req=5

pone.0138335.g006: Hypothetical model depicting a possible interaction between in-vivo rapamycin treatment and ex-vivo DC-based immunotherapy for effective balance/maintenance of different T lymphocyte activities in suppression of mammary carcinoma metastasis.
Mentions: Relevant to these rapamycin-mediated Treg cell activities,[41] in our previous and present studies we showed that shikonin can effectively induce the expression of specific DAMPs, which can in turn activate caspase cascades in treated B16 and 4T1 cells.[11] In combination with DAMPs, shikonin-induced TCL can activate DCs to a full level of phenotypic and functional maturation, which in turn can promote the development of Th1 cells and the induction of cytotoxic T lymphocyte activities and their secretory expression of a specific Th1 cytokine, IFN-γ (Fig 3D). Together, these activities, and in combination with the decrease in MDSC and Treg cell activities (Fig 5), we believe, may contribute to a highly efficacious retardation of tumor growth and prolong the survival of test mice. Based on these findings, we propose a hypothetical model (Fig 6) to describe the possible immuno-cellular mechanisms by which a dendritic cell-based immunotherapeutic vaccine, when administered concomitantly with rapamycin in vivo, may provide a beneficial effect to counter balance, offset and maintain the activities of specific subsets of T lymphocytes, useful for treatment of cancer patients. Among the different phytochemicals tested in this study and our previous investigation,[11] shikonin shows the highest activity in promotion of ICD in treated tumor cells, we therefore consider that further clinical evaluation of shikonin in human immune cell-based therapy is warranted.

Bottom Line: Suppression of tumor metastasis is a key strategy for successful cancer interventions.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus