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 Fc gamma R 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.