Premium
Improving the in vivo Persistence, Distribution and Function of Cytotoxic T Lymphocytes by Inhibiting the Tumor Immunosuppressive Microenvironment
Author(s) -
Xu W.,
Cai J.,
Li S.,
Zhang H.,
Han J.,
Wen M.,
Wen J.,
Gao F.
Publication year - 2013
Publication title -
scandinavian journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.934
H-Index - 88
eISSN - 1365-3083
pISSN - 0300-9475
DOI - 10.1111/sji.12065
Subject(s) - cytotoxic t cell , tumor microenvironment , perforin , cancer research , granzyme b , in vivo , immunotherapy , effector , adoptive cell transfer , immunology , cyclophosphamide , cd8 , biology , immune system , chemistry , t cell , in vitro , chemotherapy , biochemistry , microbiology and biotechnology , genetics
Adoptive cell transfer immunotherapy of malignant tumors has the problem of symbiosis between effector cells and tumor cells, a short in vivo residence time, and a poor killing efficiency of effector cells. Thus, releasing effector cells from the cancer immunosuppressive microenvironment and improving their effective time and functional status in vivo would seem to be ideal strategies for facilitating immunotherapy. Low‐dose cyclophosphamide administration can effectively break immunotolerance by inhibiting regulatory T cells. In the present study, in order to verify whether the persistence, distribution and function of effector cells can be improved by inhibiting immunosuppressive microenvironment, low‐dose cyclophosphamide was previously intraperitoneally injected into melanoma‐bearing C 57 BL /6 mice, thereafter, CFSE ‐labeled cytotoxic T lymphocytes were transfused intravenously, and their effective time, distributive pattern, and killing efficiency in different groups were observed by measuring the fluorescence intensity and cell cycle of cytotoxic T lymphocytes distributed in various organs, in comparison with tumor growth. We found down‐regulating T regs in vivo can simultaneously reduce the levels of interleukin‐10 and transforming growth factor‐β. Migration and distribution of cytotoxic T lymphocytes in vivo was found to vary with time. Inhibition of immunotolerance can significantly improve the persistence, distribution, and function of cytotoxic T lymphocytes. Correspondingly, significantly higher secretion of perforin, granzyme B , IL ‐2, and IFN ‐γ in tumor tissues with decreased tumor growth was seen in the cyclophosphamide injection group than in the control group. Our study may provide useful information on the cyclophosphamide‐mediated mechanism for facilitating tumor immunotherapy by inhibiting the immunosuppressive tumor microenvironment.