Radiation induced abscopal antitumor effect

«Radiation and Risk», 2023, vol. 32, No. 2, pp.110-119

DOI: 10.21870/0131-3878-2023-32-2-110-119

Authors

Grivtsova L.Y. – Head of Dep., C. Sc., Med., D. Sc., Biol.
Isaeva V.G. – Lead. Researcher, C. Sc., Biol. Contacts: 4 Korolyev str., Obninsk, Kaluga region, Russia, 249035. Tel.: 8-910-910-7228; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.
Zhovtun L.P. – Researcher
Samborsky S.M. – Lab. Assistant
Ivanov S.A. – Director, Corr. Member of RAS, MD, Prof. of PFUR Dep. A. Tsyb MRRC.
Kaprin A.D. – General Director, Director of P. Hertsen MORI, Head of PFUR Dep., Academician of RAS, MD, Prof. NMRRC.
¹ A. Tsyb MRRC, Obninsk
² NMRRC, Obninsk
³ Peoples' Friendship University of Russia, Moscow
⁴ P. Hertsen MORI, Moscow

Abstract

Radiation therapy is a cancer treatment that causes direct death of cancer cells, however there is a number of reports on anticancer effect of radiotherapy, that may be considered as tumor regression at sites that are outside the irradiated volume, this phenomenon was called as abscopal antitumor effect. The article presents results of the model study of the abscopal antitumor effect. The model of very aggressive ascitic mammary tumor “Ehrlich ascites carcinoma” (EAC) was used for the study. First, one-step bilateral grafting of EAC cells to mice hind extremities was performed, the following step was the formation of tumor contralateral nodes in the hips. In 5 days after the cells transplanta-tion, the right (target) node was locally irradiated with ⁶⁰Co gamma rays with a dose of 30 Gy. The growth of the left (non-target) and the target tumor nodes was watched during 20 days after irradiation. It was found that local irradiation of the right tumor node with a dose of 30 Gy at an early stage of tumor growth caused inhibition of the left, non-target tumor node growth from 10 to 49% relative to the growth of the tumor nodes in the control group of the tumor bearing mice. In order to reduce the dose burden in this model, the impact of fractionated irradiation with single dose of 10 Gy, to a total dose of 30 Gy on the abscopal effect was studied. The ability of the immune system of the mice with transplanted tumors in both hips and the irradiated target tumor node to respond to an antigenic stimulus was studied. The study results are the following: the immune system of mice, with a transected tumor in both thighs and subsequent gamma-ray irradiation of the target tumor node at a dose of 30 Gy respond to the antigenic stimulus; radiation doses to the target tumor node are crucial in achieving the abscopal effect; the use of complementary therapeutic methods, such as targeted therapy or immunotherapy, will increase the probability of the abscopal effect achieving.

Key words
abscopal effect, ionizing radiation, experimental animals, dose fractionation, antibody-forming cells, inbred mice, Ehrlich carcinoma, contralateral nodes, target tumor, tumor regression, thymus-dependent antigen.

References

1. Lugade A.A., Moran J.P., Gerber S.A., Rose R.C., Frelinger J.G., Lord E.M. Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor. J. Immunol., 2005, vol. 174, no. 12, pp. 7516-7523.

2. Burnette B.C., Liang H., Lee Y., Chlewicki L., Khodarev N. N., Weichselbaum R.R., Fu Y.-X., Auh S.L. The efficacy of radiotherapy relies upon induction of type I interferon-dependent innate and adaptive immunity. Cancer Res., 2011, vol. 71, no. 7, pp. 2488-2496.

3. Nishisaka N., Maini A., Kinoshita Y., Yasumoto R., Kishimoto T., Jones R.F., Morse P., Hillman G.G., Wang C.Y., Haas G.P. Immunotherapy for lung metastases of murine renal cell carcinoma: synergy between radiation and cytokine-producing tumor vaccines. J. Immunother., 1999, vol. 22, no. 4, pp. 308-314.

4. Filatenkov A., Baker J., Mueller A.M., Kenkel J., Ahn G.-O., Dutt S., Zhang N., Kohrt H., Jensen K., Dejbakhsh-Jones S., Shizuru J.A., Negrin R.N., Engleman E.G., Strober S. Ablative tumor radiation can change the tumor immune cell microenvironment to induce durable complete remissions. Clin. Cancer Res., 2015, vol. 21, no. 16, pp. 3727-3739.

5. Schaue D., Ratikan J.A., Iwamoto K.S., McBride W.H. Maximizing tumor immunity with fractionated radia-tion. Int. J. Radiat. Oncol. Biol. Phys., 2012, vol. 83, no. 4, pp. 1306-1310.

6. Mole R.H. Whole body irradiation – radiobiology or medicine? Br. J. Radiol., 1953, vol. 26, no. 305, pp. 234-241.

7. Andrews J.R. The radiobiology of human cancer radiotherapy. Baltimore, MD, Univ. Park Press, 1978. 591 p.

8. Hu Z.I., McArthur H.L., Ho A.Y. The abscopal effect of radiation therapy: what is it and how can we use it in breast cancer? Curr. Breast Cancer Rep., 2017, vol. 9, no. 1, pp. 45-51.

9. Siva S., MacManus M.P., Martin R.F., Martin O.A. Abscopal effects of radiation therapy: a clinical review for the radiobiologist. Cancer Lett., 2015, vol. 356, no. 1, pp. 82-90.

10. Postow M.A, Callahan M.K., Barker C.A., Yamada Y., Yuan J., Kitano S., Mu Z, Rasalan T., Adamow M., Ritter E., Sedrak C., Jungbluth A.A., Chua R., Yang A.S., Roman R.-A., Rosner S., Benson B., Allison J.P., Lesokhin A.M., Gnjatic S., Wolchok J.D. Immunologic correlates of the abscopal effect in a patient with melanoma. N. Engl. J. Med., 2012, vol. 366, no. 10, pp. 925-931.

11. Wersall P.J., Blomgren H., Pisa P., Lax I., Kälkner K.-M., Svedman C. Regression of non-irradiated metastases after extracranial stereotactic radiotherapy in metastatic renal cell carcinoma. Acta Oncol., 2006, vol. 45, no. 4, pp. 493-497.

12. Ohba K., Omagari K., Nakamura T., Ikuno N., Saeki S., Matsuo I., Kinoshita H., Masuda J., Hazama H., Sakamoto I., Kohno S. Abscopal regression of hepatocellular carcinoma after radiotherapy for bone metas-tasis. Gut., 1998, vol. 43, no. 4, pp. 575-577.

13. Golden E.B., Chhabra A., Chachoua A., Adams S., Donach M., Fenton-Kerimian M., Friedman K., Ponzo F., Babb J.S., Goldberg J., Demaria S., Formenti S.C. Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-princi-ple trial. Lancet Oncol., 2015, vol. 16, no. 7, pp. 795-803.

14. Wu L., Wu M.O., De la Maza L., Yun Z., Yu J., Zhao Y., Cho J., Perrot M. Targeting the inhibitory receptor CTLA-4 on T cells increased abscopal effects in murine mesothelioma model. Oncotarget, 2015, vol. 6, no. 14, pp. 12468-12480.

15. Chakravarty P.K., Guha C., Alfieri A., Beri V., Niazova Z., Deb N.J., Fan Z., Thomas E.K., Vikram B. Flt3L therapy following localized tumor irradiation generates long-term protective immune response in metastatic lung cancer: its implication in designing a vaccination strategy. Oncology, 2006, vol. 70, no. 4, pp. 245-254.

16. Younes E., Haas G.P., Dezso B., Ali E., Maughan R.L., Kukuruga M.A., Montecillo E., Pontes J.E., Hillman G.G. Local tumor irradiation augments the response to IL-2 therapy in a murine renal adenocarci-noma. Cell Immunol., 1995, vol. 165, no. 2, pp. 243-251.

17. Grivtsova L.Yu., Isaeva V.G., Zhovtun L.P., Ivanov S.A., Kaprin A.D. Sposob induktsii abskopal'nogo protivoopukholevogo effekta v eksperimental'noj modeli kartsinomy Erlikha. Patent na izobretenie 2736120 C2, 11.11.2020, Zayavka №2020115487 ot 07.05.2020 [A method for inducing abscopal antitumor effect in an experimental model of Ehrlich's carcinoma. Patent for invention 2736120 C2, 11/11/2020. Application No. 2020115487 dated 05/07/2020].

18. Cunnigham A.J. A method of increased sensitivity for the testing single antibody-forming cells. Nature, 1965, vol. 207, no. 5001, pp. 1106-1107.

Full-text article (in Russian)