Anti-tumor Immune Regulation Of Interleukin-33 And Its Application Potential

Background:Interleukin-33(IL-33)belongs to the IL-1 family and plays an important role in both innate and acquired immunity.In viral infection,IL-33 was found to promote cytotoxic T lymphocyte(CTL)responses and clear infected cells.In tumor immune responses,IL-33 activates anti-tumor immune responses by promoting the function of natural killer(NK)cells,dendritic cells,and CTL cells in certain tumors,thereby inhibiting the tumor growth.Tumor vaccine is a promising tumor immunotherapy strategy,but currently lacks significant clinical efficacy.One of the possible reasons is the establishment of tumor system and local immunosuppressive mechanism,which limits the production of vaccine-induced anti-tumor effector cells and the ability of anti-tumor.Chemotherapy is an important clinical treatment for cancer.In addition to directly killing tumor cells,chemotherapy drugs may also stimulate anti-tumor immunity by causing the Immunogenic cell death(ICD)of tumor cells.The immune regulation of IL-33 combined with vaccine or chemotherapeutic drugs induces tumor cells ICD to stimulate the production of anti-tumor effector cells,which may obtain synergistic effects and achieve stronger tumor intervention.Objectives:This study aims to investigate the effect of exogenous IL-33 on anti-tumor immunity in mice by using TC-1 tumor model,and to investigate the anti-tumor effect of recombinant IL-33 combined with chemotherapy drugs and tumor antigen-specific HPV 16 therapeutic vaccine,then provides new ideas and strategies for tumor immunotherapy.Methods:Firstly,the effects of exogenous administration of recombinant IL-33 ontumor growth and immune responses in different stages of tumor growth were investigated in TC-1 tumor model of C57BL/6 mouse.Then,the tumor-bearing mice with the tumor diameter as 5-6 mm were injected intratumorally with different concentrations of four chemotherapeutic drugs to investigate tumor growth,body weight changes and mortality to screen out appropriate chemotherapeutic drugs and their working concentrations,meanwhile,the tumor cells were treated with different chemotherapeutic drugs in vitro,and examined by flow cytometry to observe its apoptosis and ICD of tumor cells.Finally,combined intervention of exogenous il-33 with intramedullary injection of chemotherapy drugs and recombinant hepatitis b core antigen virus-like particle(VLPs)vaccine(HBcAg/e749-57 VLPs)presented with HPV16 E7 peptide epitopes respectively was performed with therapeutic immunological strategies when the tumor was fully established.Results:The intervention of recombinant IL-33 in the early stage of tumor transplantation has the most significant inhibitory eflfect on TC-1 tumors in mice.When the tumor diameter reaches 2-3 mm and 5-6 mm,the intervention effect of IL-33 is weakened.When the tumor grows to 5-6mm,mice are injected intratumorally with four different chemotherapeutic drugs,and the results show that the chemotherapeutic drug oxaliplatin(OXA)significantly inhibits TC-1 tumor growth and is safe for mice;The in vitro treatment of OXA on TC-1 tumor cells can significantly promote apoptosis and effectively induce membrane transport of the ICD key molecule calreticulin(CRT).In the therapeutic intervention of tumor-bearing mice,the combination intervention of exogenous IL-33 and OXA intratumoral injection significantly inhibited tumor cell growth and stimulated strong tumor antigen-specific CTLs/Thl type cellular immunity responses,significantly inhibited the production of MDSC cells,and combined intervention significantly promoted the infiltration of CTLs in tumors.In addition,the combination intervention of exogenous IL-33 and therapeutic HPV vaccine showed a more significant and sustained tumor growth inhibition than the intervention alone,and stimulated a stronger tumor antigen-specific CTLs/Thl cellular immune responses,and significant inhibition of MDSC and Tree cells production.Although IL-33 intervention alone enhanced tumor infiltration in MDSC cells.However,the aggregation of MDSC was not promoted in a joint intervention with HPV therapeutic vaccine.Conclusions:Exogenous IL-33 intervention alone can effectively regulate tumor immune response and significantly inhibit tumor growth,and it also can coordinate the anti-tumor effect of chemotherapy drugs or therapeutic HPV vaccines,and provide the new strategy of the clinical treatment for tumors.