Etoposide activates CD8+ T cell anti-tumor immunity in osteosarcoma through MHC I upregulation via tumor-secreted IL-33 mediated signaling

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.