Immunology in radiotherapy

Radiotherapy

Assembled by Norman Reppingen (keine@sinnlose.info)

Immunity in Cancer

Outline

•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

Further Reading & more figures: