Carbonic anhydrase 2-derived drug-responsive domain regulates membrane-bound cytokine expression and function in engineered T cells.

ABSTRACT: Adoptive cell therapies (ACT) have shown reduced efficacy against solid tumor malignancies compared to hematologic malignancies, partly due to the immunosuppressive nature of the tumor microenvironment (TME). ACT efficacy may be enhanced with pleiotropic cytokines that remodel the TME; however, their expression needs to be tightly controlled to avoid systemic toxicities. Here we show T cells can be armored with membrane-bound cytokines with surface expression regulated using drug-responsive domains (DRDs) developed from the 260-amino acid protein human carbonic anhydrase 2 (CA2). The CA2-DRD can be stabilized in vitro and in vivo with the FDA-approved small-molecule CA2 inhibitor acetazolamide (ACZ). We develop conditional degrons using library-based screening of mutants and show character

SUBMITTER: Inniss MC 

PROVIDER: S-EPMC11718131 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature