Induction of immunogenic cell death by radiation-upregulated karyopherin alpha 2 in vitro.
Accumulating evidence suggests the potential for radiation therapy to generate antitumor immune responses against tumor cells by inducing immunogenic cell death and phenotypic changes. We recently found that ionizing radiation upregulated karyopherin α2 (KPNA2) in HT-29 colorectal tumor cells using quantitative proteomic analysis. To determine whether this increased KPNA2 could function as a damage-associated molecular pattern to induce antitumor immune responses, mouse bone-marrow-derived dendritic cells (BMDCs) were treated with KPNA2. KPNA2 enhanced the surface expression of CD40, CD54, CD80, CD86, and MHC class I/II on BMDCs. DCs treated with KPNA2 exhibited increased secretion of pro-inflammatory cytokines such as IL-1β, IL-6, IL-12, IL-23, and TNF-α. Co-culture of CD4(+) T cells and KPNA2-treated DCs resulted in induction of Th1/17 cytokines (IFN-γ and IL-17) and reduction of TGF-β production. Moreover, KPNA2-treated DCs were capable of increasing granzyme B and perforin expression in cytotoxic T lymphocytes. These results demonstrated that radiation-induced dying colorectal cancer cells released considerable amounts of KPNA2 that induce the maturation and activation of DCs for synergistic antitumor effect of radiation.
Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Republic of Korea.
Kyung-Hee
KH
Song
Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Republic of Korea.
Seung-Youn
SY
Jung
Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Republic of Korea.
Seong-Mook
SM
Kang
Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Republic of Korea.
Mi-Hyoung
MH
Kim
Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Republic of Korea.
Jiyeon
J
Ahn
Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Republic of Korea.
Sang-Gu
SG
Hwang
Department of Biotechnology, CHA University, Gyeonggi-do 11160, Republic of Korea.
Jun-Ho
JH
Lee
Department of Biotechnology, CHA University, Gyeonggi-do 11160, Republic of Korea. Electronic address: dslim@cha.ac.kr.
Dae-Seog
DS
Lim
Low-Dose Radiation Research Team, Radiation Health Institute, Korea Hydro & Nuclear Power Co., Ltd., Seoul 01450, Republic of Korea.
Seon Young
SY
Nam
Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Republic of Korea. Electronic address: immu@kirams.re.kr.
Jie-Young
JY
Song
D000818:Animals; D016923:Cell Death / Q000502:physiology / Q000528:radiation effects; D002454:Cell Differentiation / Q000502:physiology / Q000528:radiation effects; D049109:Cell Proliferation / Q000502:physiology / Q000528:radiation effects; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000473:pathology / Q000532:radiotherapy*; D003713:Dendritic Cells / Q000276:immunology* / Q000528:radiation effects; D005260:Female; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009687:Nuclear Proteins / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000528:radiation effects; D015854:Up-Regulation / Q000528:radiation effects; D028901:alpha Karyopherins / Q000276:immunology* / Q000378:metabolism
C490630:KPNA2 protein, human; C490631:Kpna2 protein, mouse; D009687:Nuclear Proteins; D028901:alpha Karyopherins
Danger signals; Dendritic cells; Immunogenic cell death; Ionizing radiation; Karyopherin α2