Journal for immunotherapy of cancer · 2025
Etoposide activates CD8+ T cell anti-tumor immunity in osteosarcoma through MHC I upregulation via tumor-secreted IL-33 mediated signaling.
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He Xin, Li Hanjun, Wang Haoyu, Zuo Dongqing, Dong Haoru, Mu Haoran, Yang Binghui, Tao Yining, Yang Xiyu, Zhao Bowen, Zhang Tao, Jiang Yafei, Wang Zhuoying, Wang Hongsheng, Yang Liu, Hua Yingqi, Cai Zhengdong, Wang Chongren, Sun Mengxiong, Gui Jun, Sun Wei
Аннотация
BACKGROUND: Osteosarcoma patients with high propensity for metastasis and recurrence generally encounter a poor prognosis. Despite the extensive exploration of immunotherapy, particularly the anti-programmed cell death protein 1 (anti-PD-1) antibody, in clinical trials, the efficacy remains unsatisfactory. A more profound comprehension of the resistance mechanisms and the development of innovative therapeutic strategies is imperative.
METHODS: A screening was performed for drugs capable of upregulating major histocompatibility class I (MHC I) expression among clinically common drugs. The effects of the drug on both T cells and tumor cells, as well as its combination efficacy with anti-PD-1 antibody, were studied in vitro and in vivo osteosarcoma models. The molecular mechanisms underlying these biological processes were explored via RNA sequencing analysis.
RESULTS: Etoposide was shown to upregulate the MHC I expression in osteosarcoma cells, thereby enhancing the cytotoxicity of CD8+ T cells. Interleukin-33 (IL-33) played a dominant role in etoposide-activated anti-tumor immune response. Etoposide promoted the secretion of IL-33 and augmented the expression of IL-33 binding suppression of tumorigenicity 2 (ST2) receptor, which activated the nuclear factor kappa-B signaling pathway and resulted in MHC I upregulation. Furthermore, etoposide was demonstrated to improve the therapeutic efficacy of anti-PD-1 antibody.
CONCLUSIONS: This study revealed the molecular mechanism underlying etoposide-activated CD8+ T cell anti-tumor immunity. The combination of Etoposide and anti-PD-1 antibody has the potential to benefit patients with advanced osteosarcoma.
METHODS: A screening was performed for drugs capable of upregulating major histocompatibility class I (MHC I) expression among clinically common drugs. The effects of the drug on both T cells and tumor cells, as well as its combination efficacy with anti-PD-1 antibody, were studied in vitro and in vivo osteosarcoma models. The molecular mechanisms underlying these biological processes were explored via RNA sequencing analysis.
RESULTS: Etoposide was shown to upregulate the MHC I expression in osteosarcoma cells, thereby enhancing the cytotoxicity of CD8+ T cells. Interleukin-33 (IL-33) played a dominant role in etoposide-activated anti-tumor immune response. Etoposide promoted the secretion of IL-33 and augmented the expression of IL-33 binding suppression of tumorigenicity 2 (ST2) receptor, which activated the nuclear factor kappa-B signaling pathway and resulted in MHC I upregulation. Furthermore, etoposide was demonstrated to improve the therapeutic efficacy of anti-PD-1 antibody.
CONCLUSIONS: This study revealed the molecular mechanism underlying etoposide-activated CD8+ T cell anti-tumor immunity. The combination of Etoposide and anti-PD-1 antibody has the potential to benefit patients with advanced osteosarcoma.