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Abstract
Purpose: We investigated whether adoptive cell therapy with ex vivo-activated natural killer (NK) cells enhances the therapeutic efficacy of local tumor radiation therapy (RT) using a human triple-negative breast cancer xenograft model.

Methods and materials: NK cells from healthy donors were expanded ex vivo. MDA-MB-231/Luc-GFP cells were subcutaneously implanted into the thighs of NSG mice. The animals were divided into 4 experimental groups: control, RT, NK, and RT + NK. On day 17 after tumor implantation, tumors from the RT groups were irradiated. The ex vivo-expanded NK cells were intravenously administered twice, on days 17 and 19. Primary and secondary tumors were evaluated using long-term bioluminescence imaging, and histopathology was performed on resected tumor tissue specimens.

Results: The luciferase signals of the primary tumors in the RT + NK group were significantly lower than those of comparably sized primary tumors in the RT group. The long-term migration and infiltration of NK cells into the primary tumor sites were significantly higher in RT + NK than in NK mice. Moreover, lymphatic metastasis to the axillary lymph nodes and liver and lung metastases were highly suppressed in the RT + NK group, as demonstrated by BLI and p53 immunohistochemistry. The long-term survival of the RT + NK group was significantly higher than that of the RT or NK groups.

Conclusions: Reduction in tumor burden by combining RT and systemic NK cell therapy improved the suppression of primary tumor growth, with efficient NK cell migration and penetration into the primary tumor site. Administered NK cells were maintained in the primary tissue for a significantly longer time in RT + NK group compared with NK group. Both lymphatic spread and distant metastasis to the lungs and liver were effectively suppressed by the combined therapy.

Affiliations

Kyung Won Kim  1 , Jae-Uk Jeong  2 , Kyung-Hwa Lee  3 , Tung Nguyen Thanh Uong  1 , Joon Haeng Rhee  4 , Sung-Ja Ahn  2 , Sang-Ki Kim  5 , Duck Cho  6 , Huy Phuoc Quang Nguyen  1 , Chanh Tin Pham  7 , Mee Sun Yoon  8
1 Department of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, South Korea; Department of Biomedical Science, Chonnam National University Graduate School, Gwangju, South Korea.
2 Department of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, South Korea.
3 Department of Pathology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, South Korea.
4 Department of Microbiology and Clinical Vaccine R&D Center, Chonnam National University Medical School, Gwangju, South Korea.
5 Department of Companion & Laboratory Animal Science, Kongju National University, Yesan, Republic of Korea.
6 Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
7 Department of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, South Korea; Department of Biomedical Science, Chonnam National University Graduate School, Gwangju, South Korea; Department of Biomedical Sciences, College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon, Hong Kong.
8 Department of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, South Korea; Department of Biomedical Science, Chonnam National University Graduate School, Gwangju, South Korea. Electronic address: meesunyoon@jnu.ac.kr.