Leukemic B Cell CTLA 4 Suppresses Costimulation of T Cells
The clinical benefit of CTLA 4 blockade on T cells is known, yet the impact of its expression on cancer cells remains unaddressed. We define an immunosuppressive role for tumor expressed CTLA 4 using chronic lymphocytic leukemia (CLL) as a disease model. CLL cells, among other cancer cells, are CTLA 4+ Coculture with activated human T cells induced surface CTLA 4 on primary human CLL B cells. CTLA 4 on CLL derived human cell lines decreased CD80 expression on cocultured CD80+ cells, with restoration upon CTLA 4 blockade. Coculture of CTLA 4+ CLL cells with CD80 GFP+ cell lines revealed transfer of CD80 GFP into CLL tumor cells, similar to CTLA 4+ T cells able to trans endocytose CD80. Coculture of T cells with CTLA 4+ CLL cells decreased IL 2 production. Using a human CTLA 4 knock in mouse lacking FcgR function, antitumor efficacy was observed by blocking murine CTLA 4 on tumor cells in isolation of the T cell effect and Fc mediated depletion. These data implicate tumor CTLA 4 in cancer cell mediated immunosuppression in vitro and as having a functional role in tumor cells in vivo.
The Journal of Immunology