Anti-Tumor Effects Of Allogeneic Leukocyte Infusion

Purpose:Cytokines,mAb and other biologic-based therapies are being developed as antineoplastic agents.As is well known,cancer patients are always with immune function defects.On the other hand,an intensive cell-mediated immunity wilt be initiated by a graft in the circumstances of allogeneic organ transplantation.Therefore,using the allogeneic antigen as a biological responding modifier to break the immune non-response condition could be an effective antitumor approach.This study tests the tolerance and antineoplastic activity of infusion of MHC-mismatched allogeneic leukocytes.The cells are mitotically inactivated to prevent graft-versus-host disease.Methods:After inoculation of B16-F10 or LLC tumor cells,C57BL/6 mice were treated i.v.with mitomycin C inactivated allogeneic leukocytes either alone,or combination with cyclophosphamide(Cy).Antitumor effects were evaluated by measuring tumor volume and animal survival time as well as lung weight in a spontaneous metastases model.The mechanisms of antitumor effect were analyzed by Th1,Th2 cytokines detection;CD4~+, CD8~+ T or NK cells depletion;cell-mediated cytotoxicity assay and relative/absolute number of splenocytes measurement during the treatment.Results:The infusion of inactivated allogeneic leukocytes was found to be able to induce activation and proliferation of CD4~+,CD8~+ T and NK cells and release type-1 cytokines (including IL-2 and IFN-γ) in a tumor-bearing mouse.It may in turn initiate a specific and non-specific antitumor immune response.Of note,allogeneic leukocyte infusion(ALI) caused a delayed tumor growth and a prolonged survival time in an established B16-F10 melanoma model.In addition,the therapeutic responses to ALl were potentiated by elimination of CD4~+CD25~+ regulatory T cells with injection of 30mg/Kg Cy intraperitoneally.In an LLC pulmonary spontaneous metastases model,serum concentration of TGF-B and VEGF were upregulated and thus may promote the metastases when a primary tumor has been resected.After ALl treatment,the large amount of IFN-γand IL-2 were released,and the inhibitory cytokines such as IL-10 and TGF-βwere decreased.This immune stimulation evoked a specific and non-specific antitumor immune response.As the result of these responses,lung metastases were eradicated effectively and 62.5%mice had a long-term survival. Conclusion:Administration of mitotically inactivated allogeneic leukocytes may induce activation and proliferation of enormous lymphocytes which then release large amounts of cytokines.These cytokines promoted specific and non-specific antitumor responses in mice with established or metastatic malignancies and the therapeutic responses induced by ALl were potentiated by Cy-mediated elimination of CD4~+CD25~+ regulatory T cells. In a word,transfusion of mitotically allogeneic leukocytes is a simple,safe and effective therapeutic antineoplastic approach which should be developed further as a novel antitumor strategy.