Dynamic allostery drives autocrine and paracrine TGF-β signaling TGF-β is expressed as an inactive (latent) form (L-TGF-β) and latency of mature TGF-β is determined by non-covalent association with its N-terminal prodomain cleaved by furin during biosynthesis. The prodomain encircles the mature TGF-b homodimer in a ring-shaped disulfide-linked homodimer (latency-associated peptide [LAP]), forming L-TGF-β. TGF-β can be presented on immune cell surfaces by covalent association with GARP and binding to integrin αvβ8 activates L-TGF-β1/GARP. In previous studies, the authors have uncovered that αvβ8-mediated TGF-β autocrine signaling can occur without TGF-β1 release from its latent form. In this study, the authors engineered knock-in mice globally expressing only tgfb1 with a mutated furin cleavage site that could not release TGF-β1. Interestingly, they found that these mutant tgfb1 knock-in mice survived without early lethal tissue inflammation, unlike those with TGF-β1 deficiency. Furthermore, they combined cryogenic electron microscopy with cell-based assays to reveal a dynamic allosteric mechanism of autocrine TGF-β1 signaling without release. Concretely, αvβ8 binding redistributed the intrinsic flexibility of L-TGF-β1 to expose TGF-β1 to its receptors. Moreover, the dynamic allostery revealed by the authors also explained the TGF-β3 latency/activation mechanism and why TGF-β3 functioned distinctly from TGF-β1. Collectively, dynamic-based allosteric mechanism of redistributing conformational entropy discovered in this study suggested a general mechanism of cell-cell communication. DOI: 10.1016/j.cell.2024.08.036.
A CD25×TIGIT bispecific antibody induces anti-tumor activity through selective intratumoral Treg cell depletion![]()
Wei X, et al.
Due to the suppressive function of Tregs, depletion of intratumoral Tregs is expected to induce effective antitumor immunity. However, selective depletion of tumor-infiltrating Tregs while preserving peripheral homeostasis remains a difficult issue. Leveraging the increased abundance of CD25+ TIGIT+ Tregs in the solid tumor microenvironment, the authors in this study investigated the feasibility of using CD25×TIGIT bispecific antibody (bsAb) to specifically deplete tumor-infiltrating Tregs. They firstly constructed a bsAb co-targeting mouse CD25 and TIGIT, NSWm7210. They demonstrated that NSWm7210 could enhance intratumoral Treg depletion, Teff activation, and tumor suppression as compared to the parental monotherapies in mouse models. Subsequently, they constructed a bsAb co-targeting human CD25 and TIGIT (NSWh7216), which preferentially eliminated CD25+ TIGIT+ cells over single positive cells in vitro. Importantly, they showed that NSWh7216 exhibited enhanced anti-tumor activity without toxicity of peripheral Tregs in CD25 humanized mice compared to the parental monotherapies. Collectively, CD25×TIGIT bsAbs developed in this study demonstrated potent antitumor efficacy of through selective depletion of intratumoral Tregs.
DOI: 10.1016/j.ymthe.2024.09.010.
Editor & Reviewer: Congci Yu
