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Abstract
Most glioblastomas frequently recur at sites of radiotherapy, but it is unclear if changes in the tumor microenvironment due to radiotherapy influence glioblastoma recurrence. Here, we demonstrate that radiation-induced senescent glioblastoma cells exhibit a senescence-associated secretory phenotype that functions through NFκB signaling to influence changes in the tumor microenvironment, such as recruitment of Ly6G+ inflammatory cells and vessel formation. In particular, Ly6G+ cells promote conversion of glioblastoma cells to glioblastoma stem cells (GSCs) through the NOS2-NO-ID4 regulatory axis. Specific inhibition of NFκB signaling in irradiated glioma cells using the IκBα super repressor prevents changes in the tumor microenvironment and dedifferentiation of glioblastoma cells. Treatment with Ly6G-neutralizing antibodies also reduces the number of GSCs and prolongs survival in tumor-bearing mice after radiotherapy. Clinically, a positive correlation exists between Ly6G+ cells and the NOS2-NO-ID4 regulatory axis in patients diagnosed with recurrent glioblastoma. Together, our results illustrate important roles for Ly6G+ inflammatory cells recruited by radiation-induced SASP in cancer cell dedifferentiation and tumor recurrence.

Author information

Jeon HY1,2, Ham SW1,2, Kim JK1,2, Jin X1,2, Lee SY1, Shin YJ3,4, Choi CY1,2, Sa JK4, Kim SH5, Chun T1,2, Jin X6,7, Nam DH3,4,8, Kim H9,10,11.
1
Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
2
Institute of Animal Molecular Biotechnology, Korea University, Seoul, Republic of Korea.
3
Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
4
Institute for Refractory Cancer Research, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Republic of Korea.
5
Department of Pathology, College of Medicine, Yonsei University, Seoul, Republic of Korea.
6
Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
7
Institute of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
8
Department of Health Science & Technology, Samsung Advanced Institute for Health Science & Technology, Sungkyunkwan University, Seoul, Republic of Korea.
9
Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea. hg-kim@korea.ac.kr.
10
Institute of Animal Molecular Biotechnology, Korea University, Seoul, Republic of Korea. hg-kim@korea.ac.kr.
11
Department of Medical Engineering, College of Medicine, Korea University, Seoul, Republic of Korea. hg-kim@korea.ac.kr

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