title: CD8 engineered cytotoxic T cells reprogram melanoma tumor environment.
abstract: Cytotoxic T lymphocytes (CTL) from CD8β-deficient mice have powerful FasL-mediated cytotoxicity and IFNγ responses, but ablated Ca2+and NFAT signaling, which can be restored by transduction with CD8β. Upon infection with lymphocytic choriomeningitis virus (LCMV), these cells yielded GP33-specific CTL (CD8βR) that exhibited high FasL/Fas-mediated cytotoxicity, IFNγ 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 CD8βR CTL perished. Our study demonstrates that the synergistic combination of strong Fas/FasL mediated cytotoxicity, IFNγ and CXCL9 and 10 responses endows adoptively transferred CTL to reprogram the tumor environment and to thus enable the generation of endogenous, tumoricidal immunity.
authors.affiliation: Ludwig Center for Cancer Research, University of Lausanne , Epalinges, Switzerland.
authors.forename: Julie
authors.initials: J
authors.lastname: Leignadier
authors.affiliation: Department of Biochemistry, University of Lausanne , Epalinges, Switzerland.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Favre
authors.affiliation: Department of Biochemistry, University of Lausanne , Epalinges, Switzerland.
authors.forename: Sanjiv A
authors.initials: SA
authors.lastname: Luther
authors.affiliation: Ludwig Center for Cancer Research, University of Lausanne , Epalinges, Switzerland.
authors.forename: Immanuel F
authors.initials: IF
authors.lastname: Luescher
keywords: B16 melanoma; CD8+ T cell; FasL; IFNγ; chemokines