Efficacy of CTLA-4 checkpoint therapy is dependent on IL-21 signaling to mediate cytotoxic reprogramming of PD-1⁺CD8⁺ T cells

The mechanisms underlying the efficacy of anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) therapy are incompletely understood. Here, by immune profiling responding PD-1^(+)CD8^(+) T (T(Resp)) cell populations from patients with advanced melanoma, we identified differential programming of T(Resp) cells in response to combination therapy, from an exhausted toward a more cytotoxic effector program. This effect does not occur with …