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•The role of immunity in radiotherapy
•A model in a nutshell
•Enabling success
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• Immunity in radiotherapy
10.1158/0008-5472.CAN-08-0427Kroemer & Zitvogel et al., 2008
Outline
• Immunity in radiotherapy
•Dependence on CD8+ cells / DC
•Vaccination / Radiation
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Radiotherapy Promotes Tumor-Specific Effector CD8+ T Cells via Dendritic Cell Activation
10.4049/jimmunol.1200563Maries van den Broek et al., 2012
One day before RT (10 Gy), DC or CD8+ cells were depleted.
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B16gp
Enhanced antitumor effect of dendritic cell based immunotherapy after intratumoral injection of radionuclide Ho-166 against B16 melanoma
10.1016/j.imlet.2006.03.007Min-Geol Lee et al., 2006
Rechallenge resistance:
Ho-166 = ß - Emitter; t1/2 = 26.76 h 7
• Cell intrinsic
• Immune mediated
A model in a nutshell
A model in a nutshell
10.1016/j.molmed.2013.05.007
• Cell intrinsic
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A model in a nutshell
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• Immune mediated
A model in a nutshell
Murine mammary carcinoma HE stained, 96 h after 5 Gy of γ irradiation.Stephen L. Shiao & Lisa M. Coussens, 2010
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Radiotherapy Promotes Tumor-Specific Effector CD8+ T Cells via Dendritic Cell Activation
10.4049/jimmunol.1200563Maries van den Broek et al., 2012
One day before RT (10 Gy), DC or CD8+ cells were depleted.
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B16gp
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10.1016/j.molmed.2013.05.007
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Enabling success
•Breaking Immune Suppression
•TGF-ß & STAT3
•Experiment proposal
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10.1016/j.molmed.2013.05.007
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10.1016/j.molmed.2013.05.007Marco Durante, Norman Reppingen et al., 2013
Inflammatory pathways reassorted
Two examples:
•DC therapy & TGF - siRNA at the tumor
•DC therapy with sunitinib
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Gene silencing of TGF-ß1 enhances antitumor immunity induced with a dendritic cell vaccine by reducing tumor-associated regulatory T cells
10.1007/s00262-011-1188-yConroy, Mills et al., 2012
DC loaded with hs/irr B16F10 cells and stimulated with CpG (TLR9 Agon.) (3x)siRNA applied to tumor (9x).
Tumors removed on day 21 & stained for CD4, CD8 and analyzed by FACS.
10.1016/j.ccr.2005.10.012
Sunitinib facilitates the activation and recruitment of therapeutic anti-tumor immunity in concert with specific vaccination
10.1002/ijc.25863
Sunitinib = STAT3 inhibitor in clinical routine.
MO5 = B16 expressing OVA
Bose & Storkus et al., 2010
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Hypothesis: Antagonizing immune suppressive pathways can turn Radiotherapy into a versatile cancer immune therapy, furnishing quick, cheap and sustainable cure.
10.1016/j.molmed.2013.05.007Marco Durante, Norman Reppingen et al., 2013
LiteratureLionel Apetoh et al.: Molecular interactions between dying tumor cells and the innate immune system determine the efficacy of conventional anticancer therapies. Cancer Res, 68(11):4026–30, 6 2008, 10.1158/0008-5472.CAN-08-0427.
A. Gupta et al.: Radiotherapy promotes tumor-specific effector cd8+ t cells via dendritic cell activation. The Journal of Immunology, 189(2), 558–566, 2012, 10.4049/jimmunol.1200563
Lisa M. Coussens et al.: The tumor-immune microenvironment and response to radiation therapy. J Mammary Gland Biol Neoplasia, 15(4):411–21, 2010, 10.1007/s10911-010-9194-9.
Lee et al.: Enhanced antitumor effect of dendritic cell based immunotherapy after intratumoral injection of radionuclide Ho-166 against B16 melanoma. Immunology Letters 106 (2006) 19–26, 10.1016/j.imlet.2006.03.007
Mills et al.: Gene silencing of TGF-ß1 enhances antitumor immunity induced with a dendritic cell vaccine by reducing tumor-associated regulatory T cells, Cancer Immunol Immunother (2012) 61:425–431; 10.1007/s00262-011-1188-y
Anamika Bose et al.: Sunitinib facilitates the activation and recruitment of therapeutic anti-tumor immunity in concert with specific vaccination. Int. J. Cancer: 129, 2158–2170 10.1002/ijc.25863
James W. Hodge et al: Consequence of dose scheduling of sunitinib on host immune response elements and vaccine combination therapy, Int. J. Cancer: 130, 1948–1959 (2012), 10.1002/ijc.26219
Marco Durante et al: Immunologically augmented cancer treatment using modern radiotherapy, Trends in Molecular Medicine, 10.1016/j.molmed.2013.05.007
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