CD8 engineered cytotoxic T cells reprogram melanoma tumor environment.

Cytotoxic T lymphocytes (CTL) from CD8 beta-deficient mice have powerful FasL-mediated cytotoxicity and IFN responses, but ablated Ca2+ and NFAT signaling, which can be restored by transduction with CD8 beta. Upon infection with lymphocytic choriomeningitis virus (LCMV), these cells yielded GP33-specific CTL (CD8 beta R) that exhibited high FasL/Fas-mediated cytotoxicity, IFN gamma 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 beta R CTL perished. Our study demonstrates that the synergistic combination of strong Fas/FasL mediated cytotoxicity, IFN gamma and CXCL9 and 10 responses endows adoptively transferred CTL to reprogram the tumor environment and to thus enable the generation of endogenous, tumoricidal immunity.