2024
Oncoimmunology. 2024 Sep 22;13(1):2406576. doi: 10.1080/2162402X.2024.2406576. eCollection 2024.
Immune priming and induction of tertiary lymphoid structures in a cord-blood humanized mouse model of gastrointestinal stromal tumor
Cancer Microenvironment Laboratory, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia. Translational Cancer Research Program, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia. Imaging & Therapy Laboratory, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia. Department of Anatomical Pathology, PathWest QEII Medical Centre, Perth, Western Australia. Department of General Surgery, Fiona Stanley Hospital, Western Australia, Australia.6Division of Surgery, School of Medicine, University of Western Australia, Western Australia, Australia. Sir Charles Gairdner Hospital, QEII Medical Centre, Perth, Western Australia, Australia. Division of Internal Medicine, School of Medicine, University of Western Australia, Western Australia, Australia. Division of Obstetrics and Gynaecology, Faculty of Medicine, Dentistry, and Health Sciences, The University of Western Australia, Perth, Western Australia, Australia.
Service type: Stock strains
Abstract
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.
Keywords: Gastrointestinal tumor (GIST); LIGHT (TNFS14); humanized mice; tertiary lymphoid structures (TLS); vascular targeting.
