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Survivin the battle against immunosuppression.

Manuel ER, Blache CA, Ellenhorn JD, Diamond DJ - Oncoimmunology (2012)

Bottom Line: Improving on the limited success of cancer immunotherapy requires new approaches to inhibit immunosuppressive pathways initiated by tumor cells to "escape" protective immunity.One unique approach utilizes Salmonella for systemic delivery of inhibitory RNA, targeting the immunosuppressive molecule Stat3, and a Survivin vaccine to suppress growth of aggressive murine tumors.

View Article: PubMed Central - PubMed

Affiliation: Division of Translational Vaccine Research; City of Hope; Duarte, CA USA.

ABSTRACT
Improving on the limited success of cancer immunotherapy requires new approaches to inhibit immunosuppressive pathways initiated by tumor cells to "escape" protective immunity. One unique approach utilizes Salmonella for systemic delivery of inhibitory RNA, targeting the immunosuppressive molecule Stat3, and a Survivin vaccine to suppress growth of aggressive murine tumors.

No MeSH data available.


Related in: MedlinePlus

Figure 1. shStat3-ST treatment enhances Max-ST vaccination efficacy. Proposed mechanism of action by combined treatment with shStat3-ST and Max-ST. Left to right: In a B16F10 tumor-bearing mouse, shStat3-ST is first injected intravenously, followed by oral vaccination with Max-ST. Immunosuppression (red) developing from hyperactivated Stat3 expression (Stat3P+) in tumor cells and APCs is targeted by shStat3-ST (green line). Max-ST serves to boost anti-tumor responses through enhanced expression of SVN within tumor cells or APCs (green arrows) resulting in SVN antigen presentation via MHC class I. The combined treatment works synergistically to allow for tumor killing by SVN-specific CD8+ T cells (blue line) leading to tumor regression.
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Figure 1: Figure 1. shStat3-ST treatment enhances Max-ST vaccination efficacy. Proposed mechanism of action by combined treatment with shStat3-ST and Max-ST. Left to right: In a B16F10 tumor-bearing mouse, shStat3-ST is first injected intravenously, followed by oral vaccination with Max-ST. Immunosuppression (red) developing from hyperactivated Stat3 expression (Stat3P+) in tumor cells and APCs is targeted by shStat3-ST (green line). Max-ST serves to boost anti-tumor responses through enhanced expression of SVN within tumor cells or APCs (green arrows) resulting in SVN antigen presentation via MHC class I. The combined treatment works synergistically to allow for tumor killing by SVN-specific CD8+ T cells (blue line) leading to tumor regression.

Mentions: In our study published in Cancer Research,3 we utilized the unique properties of Salmonella as a tumor-homing vector and as a vaccine. This gave us the flexibility to target immunosuppressive molecules in the tumor using shRNA plasmid technology (shStat3-ST) and to utilize a strong Salmonella promoter to express tumor antigen for CTL induction (Max-ST) (Fig. 1). We targeted the multi-functional molecule Stat3, which has been repeatedly implicated in tumor survival, proliferation, angiogenesis and metastasis while promoting expression of immunosuppressive factors, Treg expansion and inhibition of TH1 immunostimulatory molecules.4 Our logic in trying to inactivate Stat3 function was supported by promising results of small-molecule and siRNA inhibitors used in tumors with hyperactivated Stat3 phenotypes.5 We combined inactivation of Stat3 with vaccination using Salmonella expressing a versatile TAA known as Survivin (SVN). SVN is a member of the inhibitor of apoptosis (IAP) protein family and possesses ideal TAA properties: undetectable expression in non-cancerous adult tissues, overexpression in most human tumors, and induces cytotoxic T lymphocytes.6 SVN is regulated by many pathways including Stat3 transactivation through IL-11 signaling.7


Survivin the battle against immunosuppression.

Manuel ER, Blache CA, Ellenhorn JD, Diamond DJ - Oncoimmunology (2012)

Figure 1. shStat3-ST treatment enhances Max-ST vaccination efficacy. Proposed mechanism of action by combined treatment with shStat3-ST and Max-ST. Left to right: In a B16F10 tumor-bearing mouse, shStat3-ST is first injected intravenously, followed by oral vaccination with Max-ST. Immunosuppression (red) developing from hyperactivated Stat3 expression (Stat3P+) in tumor cells and APCs is targeted by shStat3-ST (green line). Max-ST serves to boost anti-tumor responses through enhanced expression of SVN within tumor cells or APCs (green arrows) resulting in SVN antigen presentation via MHC class I. The combined treatment works synergistically to allow for tumor killing by SVN-specific CD8+ T cells (blue line) leading to tumor regression.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3377007&req=5

Figure 1: Figure 1. shStat3-ST treatment enhances Max-ST vaccination efficacy. Proposed mechanism of action by combined treatment with shStat3-ST and Max-ST. Left to right: In a B16F10 tumor-bearing mouse, shStat3-ST is first injected intravenously, followed by oral vaccination with Max-ST. Immunosuppression (red) developing from hyperactivated Stat3 expression (Stat3P+) in tumor cells and APCs is targeted by shStat3-ST (green line). Max-ST serves to boost anti-tumor responses through enhanced expression of SVN within tumor cells or APCs (green arrows) resulting in SVN antigen presentation via MHC class I. The combined treatment works synergistically to allow for tumor killing by SVN-specific CD8+ T cells (blue line) leading to tumor regression.
Mentions: In our study published in Cancer Research,3 we utilized the unique properties of Salmonella as a tumor-homing vector and as a vaccine. This gave us the flexibility to target immunosuppressive molecules in the tumor using shRNA plasmid technology (shStat3-ST) and to utilize a strong Salmonella promoter to express tumor antigen for CTL induction (Max-ST) (Fig. 1). We targeted the multi-functional molecule Stat3, which has been repeatedly implicated in tumor survival, proliferation, angiogenesis and metastasis while promoting expression of immunosuppressive factors, Treg expansion and inhibition of TH1 immunostimulatory molecules.4 Our logic in trying to inactivate Stat3 function was supported by promising results of small-molecule and siRNA inhibitors used in tumors with hyperactivated Stat3 phenotypes.5 We combined inactivation of Stat3 with vaccination using Salmonella expressing a versatile TAA known as Survivin (SVN). SVN is a member of the inhibitor of apoptosis (IAP) protein family and possesses ideal TAA properties: undetectable expression in non-cancerous adult tissues, overexpression in most human tumors, and induces cytotoxic T lymphocytes.6 SVN is regulated by many pathways including Stat3 transactivation through IL-11 signaling.7

Bottom Line: Improving on the limited success of cancer immunotherapy requires new approaches to inhibit immunosuppressive pathways initiated by tumor cells to "escape" protective immunity.One unique approach utilizes Salmonella for systemic delivery of inhibitory RNA, targeting the immunosuppressive molecule Stat3, and a Survivin vaccine to suppress growth of aggressive murine tumors.

View Article: PubMed Central - PubMed

Affiliation: Division of Translational Vaccine Research; City of Hope; Duarte, CA USA.

ABSTRACT
Improving on the limited success of cancer immunotherapy requires new approaches to inhibit immunosuppressive pathways initiated by tumor cells to "escape" protective immunity. One unique approach utilizes Salmonella for systemic delivery of inhibitory RNA, targeting the immunosuppressive molecule Stat3, and a Survivin vaccine to suppress growth of aggressive murine tumors.

No MeSH data available.


Related in: MedlinePlus