Targeting Regnase-1 in B7-H3-CAR T cells reprograms the tumor microenvironment and enhances antitumor efficacy for osteosarcoma
Year: 2026
Type: article
Abstract: The microenvironment in solid tumors represents an immunosuppressive therapeutic barrier to CAR T cell therapy, and it is currently unknown whether it can be reshaped by the deletion of negative regulators in CAR T cells. To address this knowledge gap, we evaluated the intrinsic and extrinsic effects of deleting the negative regulator Regnase-1 (Reg-1) in B7-H3-CAR T cells for the immunotherapy of osteosarcoma. Reg-1 knockout (KO) improved the antitumor activity of human and murine B7-H3-CAR T cells in vivo. In immune-competent models, Reg-1 KO also endowed murine B7-H3-CAR T cells with the ability to create a proinflammatory landscape characterized by an influx of interferon gamma (IFN-γ)-producing endogenous T cells and natural killer (NK) cells and a reduction of inhibitory myeloid cells, including M2-like macrophages. Thus, deleting Reg-1 has cell- and non-cell-autonomous benefits, nominating Reg-1 KO B7-H3-CAR T cells as a promising cell product for early-phase clinical testing in patients with solid tumors.
Source: Cell Reports Medicine
Authors: Adeleye O. Adeshakin, Hao Shi, S. Scott Perry, Heather Sheppard, Phuong Nguyen, Xiang Sun, Peipei Zhou, Jean-Yves Métais, Trevor Cunningham, Anil KC, Liqing Tian, Vivek Peche, Mollie S. Prater, Deanna M. Langfitt, Carla O'Reilly, Jeoungeun J. Park, Ashley Chabot, Sheng Zhou, Azusa Matsubara, GaHyun Lee, Shengdar Q. Tsai, Shondra M. Pruett-Miller, Lindsay J. Talbot, Jason T. Yustein, Giedre Krenciute, Christopher DeRenzo, Hongbo Chi, Stephen Gottschalk
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,620
Awards: G1980380190, G4989457172, G5368822766, G8161934498, Identifying and overcoming mechanisms of resistance to effectively target the TBL1/β-catenin signaling axis for high-risk osteosarcoma, Transcriptional and metabolic heterogeneity in T cell differentiation, Modeling and targeting intrinsic and extrinsic features of Myc-driven Osteosarcoma, Cancer Center Support Grant (CCSG), Enabling immunotherapy for high-risk Group 3 medulloblastoma via systems immunology
OpenAlex ID: W7204192358