CELL INTELLIGENCE · 肿瘤细胞治疗研究

Two prominent mechanisms by which tumors fend off immune control are by constraining the ability of T cells and CAR T cells to survive and expand in the tumor, and by restraining their ability to sustain full cytotoxic capacity. We identified I B , encoded by Nfkbid , a poorly characterized I B family member, as a molecular lever that overcomes both of these constraints on anti-tumor CD8 + tumor-infiltrating lymphocytes (TILs). Nfkbid is an NFAT target gene that is expressed in CD8 + effector T cells and, at modest levels, in CD8 + TILs. We found that Nfkbid depletion impaired TIL accumulation, exacerbating the growth of solid tumors. On the other hand, ectopic I B overexpression enhanced TIL expansion, reduced the expression of exhaustion-associated transcription factors and inhibitory receptors, and elevated cytotoxic molecule production, leading to enhanced tumor control. I B has a shorter protein isoform that is identical in a core region spanning the ankyrin-repeat domain known to interact with NF B proteins, but that lacks the ~150-residue N-terminal region. We showed that the shared core region is sufficient to drive T cell accumulation, whereas the N-terminal peptide region is required for robust effector function and to counter exhaustion, underscoring that tumor-infiltrating CD8 + T cell accumulation and effector differentiation are separable programs. Our current study provides evidence that I B , an atypical member of the NF B family, is a lever to overcome two cardinal deficits that limit CD8 + TIL anti-tumor efficacy: impaired accumulation in the tumor and diminished effector function.