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

ABSTRACT: 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 anti-PD-1 monotherapy. Single-cell transcriptome and T cell receptor repertoire analysis was used to identify altered effector programming of expanding PD-1⁺CD8⁺ T cell clones with distinct regulon usage, STAT1 and STAT3 utilization and antitumor specific

SUBMITTER: Zhang Z 

PROVIDER: S-EPMC12853267 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature