Maximizing tumor immunity with fractionated radiation.
OBJECTIVE
Technologic advances have led to increased clinical use of higher-sized fractions of radiation dose and higher total doses. How these modify the pathways involved in tumor cell death, normal tissue response, and signaling to the immune system has been inadequately explored. Here we ask how radiation dose and fraction size affect antitumor immunity, the suppression thereof, and how this might relate to tumor control.


METHODS
Mice bearing B16-OVA murine melanoma were treated with up to 15 Gy radiation given in various-size fractions, and tumor growth followed. The tumor-specific immune response in the spleen was assessed by interferon-γ enzyme-linked immunospot (ELISPOT) assay with ovalbumin (OVA) as the surrogate tumor antigen and the contribution of regulatory T cells (Tregs) determined by the proportion of CD4(+)CD25(hi)Foxp3(+) T cells.


RESULTS
After single doses, tumor control increased with the size of radiation dose, as did the number of tumor-reactive T cells. This was offset at the highest dose by an increase in Treg representation. Fractionated treatment with medium-size radiation doses of 7.5 Gy/fraction gave the best tumor control and tumor immunity while maintaining low Treg numbers.


CONCLUSIONS
Radiation can be an immune adjuvant, but the response varies with the size of dose per fraction. The ultimate challenge is to optimally integrate cancer immunotherapy into radiation therapy.
Department of Radiation Oncology, David Geffen School of Medicine at UCLA, B3-109 CHS, 10833 Le Conte Avenue, Los Angeles, CA 90095-1714, USA. dschaue@mednet.ucla.edu
Dörthe
D
Schaue
Josephine A
JA
Ratikan
Keisuke S
KS
Iwamoto
William H
WH
McBride
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D019583:Dose Fractionation, Radiation; D058501:Enzyme-Linked Immunospot Assay / Q000379:methods; D005260:Female; D007371:Interferon-gamma / Q000276:immunology; D018655:Lymphocyte Count; D008546:Melanoma, Experimental / Q000276:immunology* / Q000532:radiotherapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D013154:Spleen / Q000276:immunology; D013156:Splenectomy; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D000951:Antigens, Neoplasm; D007371:Interferon-gamma; D010047:Ovalbumin