The Role And Mechanism Of T Cell Exhaustion In Cellular Immunotherapy

Background: The application of tumor immunotherapy provides a new method for the treatment of hematological tumors,which greatly improves the survival of patients.Many preclinical and clinical trials have demonstrated that the use of cytokine-induced killer cells(CIK)after hematopoietic stem cell transplantation(HSCT)not only enhances the anti-tumor effect of HSCT and prevents relapse,but also reduces the incidence of graft-versus-host disease(GVHD).rate.On this basis,this study explored the role of different sources of CIK cells in anti-tumor effects,as well as the components that play a role in anti-tumor effects and its mechanism of action,thereby expanding its application and assisting with other immunotherapies.Methods: Through clinical application,we collected information on patients treated with CIK cells after hematopoietic stem cell transplantation and established an in vitro model describing changes in CIK cells.Flow cytometry was used to detect changes in surface molecular markers before and after CIK cell culture,and how to reflect changes in cell types during CIK cell culture.The key molecules were identified by gene sequencing technology.Real-time PCR verified the changes of these key molecules in the mRNA level before and after CIK cell culture,so as to explore the mechanism of CIK cells.Results: Patients treated with CIK cells after hematopoietic stem cell transplantation have improved disease status.Flow cytometry showed that the proportion of CD3+CD56+ T cells increased during CIK cell culture,and the proportion of exhaustion index CD56+TIM-3+ T cells decreased.CD3+CD56+ T cells are the main cellular components of CIK cells.Therefore,we sorted the CD3+CD56+ T cells before and after culture and sequenced them to identify the key molecules ELANE,SERPINA1,CD177,CD300 A..Real-time PCR confirmed that the changes in ELANE mRNA levels were statistically significant before and after CIK cell culture.We found that in CIK cells,changes in T cell function are mainly changes in exhausted T cells.Therefore,the key to adoptive immunotherapy is the reversal of T cell exhaustion,which improves T cell function,thereby inhibiting GVHD and anti-tumor effects.Conclusions: Adoptive immunotherapy CIK infusion can inhibit GVHD and antitumor effect.Flow cytometry confirmed that the change of CIK cells was mainly the change of CD3+CD56+ T cells,and the key to the effectiveness of CIK was the reversal of the exhaustion state of T cells,so as to improve the function of T cells and enable them to exert the above effect.The key to T cell function is the difference in ELANE gene expression.