Immune priming and induction of tertiary lymphoid structures in a cord-blood humanized mouse model of gastrointestinal stromal tumor

• Published in: Oncoimmunology 2024-12, Vol.13 (1), p.2406576
• Main Authors: He, Bo, Dymond, Larissa, Wood, Kira H., Bastow, Edward R., Satiaputra, Jiulia, Li, Ji, Johansson-Percival, Anna, Hamzah, Juliana, Kumarasinghe, M. Priyanthi, Ballal, Mohammed, Foo, Jonathan, Johansson, Mikael, Ee, Hooi C., White, Scott W., Winteringham, Louise, Ganss, Ruth
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Disease Models, Animal; Fetal Blood - cytology; Gastrointestinal Neoplasms - immunology; Gastrointestinal Neoplasms - pathology; Gastrointestinal Neoplasms - therapy; Gastrointestinal Stromal Tumors - immunology; Gastrointestinal Stromal Tumors - pathology; Gastrointestinal Stromal Tumors - therapy; Gastrointestinal tumor (GIST); humanized mice; Humans; Immunotherapy - methods; LIGHT (TNFS14); Mice; Neovascularization, Pathologic - immunology; Neovascularization, Pathologic - pathology; Original Research; tertiary lymphoid structures (TLS); Tertiary Lymphoid Structures - immunology; Tertiary Lymphoid Structures - pathology; Tumor Microenvironment - immunology; Tumor Necrosis Factor Ligand Superfamily Member 14 - genetics; Tumor Necrosis Factor Ligand Superfamily Member 14 - metabolism; vascular targeting; Xenograft Model Antitumor Assays
• ISSN: 2162-402X; 2162-4011; 2162-402X
• DOI: 10.1080/2162402X.2024.2406576

Gastrointestinal stromal tumors (GISTs) harbor diverse immune cell populations but so far immunotherapy in patients has been disappointing. Here, we established cord blood humanized mouse models of localized and disseminated GIST to explore the remodeling of the tumor environment for improved immunotherapy. Specifically, we assessed the ability of a cancer vascular targeting peptide (VTP) to bind to mouse and patient GIST angiogenic blood vessels and deliver the TNF superfamily member LIGHT (TNFS14) into tumors. LIGHT-VTP treatment of GIST in humanized mice improved vascular function and tumor oxygenation, which correlated with an overall increase in intratumoral human effector T cells. Concomitant with LIGHT-mediated vascular remodeling, we observed intratumoral high endothelial venules (HEVs) and tertiary lymphoid structures (TLS), which resemble spontaneous TLS found in GIST patients. Thus, by overcoming the limitations of immunodeficient xenograft models, we demonstrate the therapeutic feasibility of vascular targeting and immune priming in human GIST. Since TLS positively correlate with patient prognosis and improved response to immune checkpoint inhibition, vascular LIGHT targeting in GIST is a highly translatable approach to improve immunotherapeutic outcomes.