OncoTargets and Therapy (May 2019)
Irradiation increases the immunogenicity of lung cancer cells and irradiation-based tumor cell vaccine elicits tumor-specific T cell responses in vivo
Abstract
Lumeng Luo, Minghe Lv, Xibing Zhuang, Qi Zhang, Tiankui QiaoDepartment of Oncology, Jinshan Hospital, Medical Center of Fudan University, Shanghai 201500, People’s Republic of ChinaBackground: During the past decades, great efforts have been built to develop lung cancer vaccines. Whole tumor cell lysate (TCL) are ideal sources of antigens for cancer vaccine design, which however have limited efficacy due to insufficient immunogenicity. Recently, radiotherapy has been closely related to immunotherapy. Numerous studies have demonstrated the regulatory effect of irradiation (IR) on tumor immune response.Purpose: To explore the immunogenicity modulation effect of IR on lung cancer cells.Methods: RNA-sequence and qPCR assay was used to evaluate the change of tumor antigens expression after repeated X rays radiation on A549 cells. Vaccine based on TCL of irradiated Lewis lung cancer cells (IR-LLC) was established; therapeutic effect of TCL (IR-LLC) was examined in xenografted tumor model of mice. Flow cytometry was conducted to evaluate the rate of immune cells in spleen; ELISA was used to detect the level of cytokines in plasma. Immunohistochemistry was performed to evaluate the infiltrations of T-cell in tumor tissues; TIMER analysis was used to explore the correlations between tumor antigen expressions and the abundances of immune infiltrates.Results: IR upregulated the expression of tumor antigens in A549 cells. Compared to the control group and unirradiated tumor cell vaccine, TCL(IR-LLC) had a significantly stronger anti-tumor effect in mice bearing with LLC xenografts. TCL(IR-LLC) significantly increased matured DCs and total CD4+ T cells but downregulated Tregs and PD-1+ CD8+ T cells in mice spleen; TCL(IR-LLC) vaccine upregulated the level of IFN-γ and IL-4 while decreased IL-10 in serum; increased infiltrations of CD4+ T-cells and CD8+ T-cells were observed in the tumor issues of mice immunized with TCL(IR-LLC). Tumor antigens including FN1, MFGE8, MMP2, MYL9 may contribute to the enhanced T-cell response.Conclusion: This study confirmed the immunogenicity modulation effect of IR in NSCLC cells, indicating IR might be an effective strategy to enhance the anti-tumor immunity of cancer cell vaccine.Keywords: lung cancer, whole tumor cell vaccine, irradiation, tumor antigen, T cell
