Radiotherapy can enhance the immune system's ability to fight cancer in several ways: 1) Radiation can activate dendritic cells to promote tumor-specific CD8+ T cells. 2) Both cell-intrinsic and immune-mediated mechanisms contribute to the anti-tumor effects of radiation. 3) Breaking immune suppression, such as blocking TGF-ß or STAT3, can increase the success of radiotherapy and immunotherapy combinations by turning radiation into a versatile cancer immune therapy.

1. Radiotherapy
Assembled by Norman Reppingen
(keine@sinnlose.info)
Immunity in Cancer

2. Outline
•The role of immunity in radiotherapy
•A model in a nutshell
•Enabling success
2

3. 3
•Immunity in radiotherapy

4. 10.1158/0008-5472.CAN-08-0427Kroemer & Zitvogel et al., 2008

5. Outline
•Immunity in radiotherapy
•Dependence on CD8+ cells / DC
•Vaccination / Radiation
5

6. 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.
6
B16gp

7. Enhanced antitumor effect of dendritic cell based immunotherapy
after intratumoral injection of radionuclide Ho-166 against B16 melanoma
10.1016/j.imlet.2006.03.007
Min-Geol Lee et al., 2006
Rechallenge resistance:
Ho-166 = ß - Emitter; t1/2 = 26.76 h7

8. • Cell intrinsic
• Immune mediated
A model in a nutshell

9. A model in a nutshell
10.1016/j.molmed.2013.05.007

10. • Cell intrinsic
10
A model in a nutshell

11. 11

12. 12

13. 13

14. 14

15. 15

16. 16

17. 17

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19. 19

20. • 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

21. 21

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25. 25

26. 26

27. 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.
27
B16gp

28. 28
10.1016/j.molmed.2013.05.007

29. 29
Enabling success
•Breaking Immune Suppression
•TGF-ß & STAT3
•Experiment proposal

30. 30
10.1016/j.molmed.2013.05.007

31. 31
10.1016/j.molmed.2013.05.007Marco Durante, Norman Reppingen et al., 2013
Inflammatory pathways reassorted

32. Two examples:
•DC therapy & TGF - siRNA at the tumor
•DC therapy with sunitinib
32

33. 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

34. 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

35. 35
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

36. Literature
Lionel 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: