Work

601 GARP–TGF-β1 blockade with livmoniplimab reprograms spatial tumor niches and enhances PD-1 inhibition in human tumor explants

Year: 2026

Type: conference-abstract

Abstract: Background Transforming growth factor (TGF)-β signaling promotes an immunosuppressive tumor microenvironment (TME) that dampens checkpoint therapy, anti-PD1/PDL1, response. GARP, encoded by LRRC32, is a membrane-bound receptor that complexes with latent TGF-β1 and is critical for its immunosuppressive function. Livmoniplimab (Livmo), a first-in-class monoclonal antibody (mAb), stabilizes the GARP–TGF-β1 complex and sequesters TGF-β in its inactive form. Livmo is being evaluated in clinical trials in combination with the anti–PD-1 mAb Budigalimab (Budi) in advanced solid tumors. To define the mechanism of action of Livmo and the contribution of Livmo plus Budi, we used tumor explant models with an intact tumor microenvironment (TME).Methods Fresh human tumor tissue culture platforms preserve autologous TME and immune cell content, enabling translational analysis of treatment effects. Fresh slices were cultured for 48–72 hours with Livmo ± Budi and activity was assessed by spectral flow cytometry and Luminex assays. Spatial transcriptomics were performed to characterize the distribution of GARP + cells after filtering necrotic regions and confirming sufficient tissue quality based on prespecified quality control metrics. Visium/VisiumHD were analyzed using the Giotto workflow including spatial network and neighborhood analyses and treatment groups were compared with isotype controls at both the spot and explant levels using differential pathway enrichment methods.Results and Conclusions In tumor explants, Livmo bound the GARP–TGF-β1 complex on endothelial, stromal, myeloid, and Treg cells. Livmo reduced the proportion of PD-1-expressing CD8 T-cells and increased the proportion of granzyme B (GZMB)-positive CD8 T-cells as well as GZMB secretion. Livmo plus Budi further enhanced cytokine and chemokine secretion, particularly CCL3 (MIP1α), which primarily recruits immune cells such as monocytes, T-cells and NK cells, thereby promoting immune-cell infiltration, a more inflammatory TME, and potentially anti-tumor immunity.VisiumHD analysis showed that Livmo decreased TGF-β/SMAD pathway activity in fibroblasts, myeloid cells, and T-cells, particularly in LRRC32-expessing spots and neighboring regions. Immune activation signatures, including TNF signaling significantly increased in spots within the LRRC32 niche after Budi, Livmo and combination treatments, with gradually higher significance levels. In addition, tumor-intrinsic inflammation signatures increased in the tumor-high spots in the combination treatment independent of LRRC32 proximity, suggesting that GARP-TGF-β blockade induces broader TME remodeling. Consistent with TGFβ-pathway suppression, Livmo also reduced extracellular matrix-and collagen-associated gene signatures. Overall, these data show that Livmo alone and in combination with Budi, remodels the TME and reinvigorates anti-tumor immunity.Consent AbbVie Disclosure statement: All authors are or were employees of AbbVie at the time of the study. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. No honoraria or payments were made for authorship.

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-sitc2026.0601