Harnessing TLR4 Signaling Pathways in CAR Dendritic Cells to Overcome Tumor Immune Tolerance

Solid tumors may evade immune destruction due to T-cell or dendritic cell (DC) dysfunction, and current immunotherapies face limitations in solid tumors. This project addresses these challenges by leveraging our myeloid chimeric antigen receptor (CAR) expertise to mechanistically characterize a novel DC-based immunotherapy: αB7H3-TLR4 CAR-DCs. These engineered DCs express a B7H3-specific CAR fused to the intracellular signaling domain of Toll-like receptor 4 (TLR4). Preliminary data demonstrate that αB7H3-TLR4 CAR-DCs efficiently capture tumor antigens from tumor cells expressing the tumor associated antigen B7H3, potently upregulate costimulatory molecules, and robustly cross-prime naïve tumor-specific CD8⁺ T cells, leading to complete tumor rejection and durable immune memory in a heterogenous B7H3-expressing sarcoma model. This project will dissect the distinct roles of MyD88 and TRIF signaling pathways downstream of TLR4 in these CAR-DCs. Aim 1 will define the role of MyD88 in acute T-cell priming and effector differentiation, while Aim 2 will define the role of TRIF in long-term memory and recall responses. By elucidating these mechanisms, we will provide a roadmap for rationally designing DC-based therapies that maximize both immediate tumor control and durable immune protection, ultimately leading to more effective treatments for a wide range of solid tumors. Project Number: 1R21CA313766-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Carl DeSelm | Institution: WASHINGTON UNIVERSITY, SAINT LOUIS, MO | Award Amount: $399,829 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 BTC-F (80)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11350180