CD8 engineered cytotoxic T cells reprogram melanoma tumor environment.

ABSTRACT: Cytotoxic T lymphocytes (CTL) from CD8?-deficient mice have powerful FasL-mediated cytotoxicity and IFN? responses, but ablated Ca²⁺ and NFAT signaling, which can be restored by transduction with CD8?. Upon infection with lymphocytic choriomeningitis virus (LCMV), these cells yielded GP33-specific CTL (CD8?R) that exhibited high FasL/Fas-mediated cytotoxicity, IFN? CXCL9 and 10 chemokine responses. Transfer of these cells in B16-GP33 tumor bearing mice resulted in (i) massive T cell tumor infiltration, (ii) strong reduction of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Treg) and IL-17-expressing T helper cells, (iii) maturation of tumor-associated antigen-presenting cells and (iv) production of endogenous, B16 melanoma-specific CTL that eradicated the tumor long after the transferred CD8?R CTL perished. Our study demonstrates that the synergistic combination of strong Fas/FasL mediated cytotoxicity, IFN? and CXCL9 and 10 responses endows adoptively transferred CTL to reprogram the tumor environment and to thus enable the generation of endogenous, tumoricidal immunity.

SUBMITTER: Leignadier J 

PROVIDER: S-EPMC4839323 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature