Abstract 2475: Visualization of cell to cell and cell to matrix interactions in the disruption of tumor-promoting desmoplasia by adoptive transfer of fibroblast activation protein targeted chimeric antigen receptor (CAR) T cells
التفاصيل البيبلوغرافية
العنوان:
Abstract 2475: Visualization of cell to cell and cell to matrix interactions in the disruption of tumor-promoting desmoplasia by adoptive transfer of fibroblast activation protein targeted chimeric antigen receptor (CAR) T cells
The efficacy of chimeric antigen receptor (CAR) T-cell therapy in solid tumors is limited by inefficient T-cell infiltration, localization and hypofunctionality within the tumor microenvironment. Prior studies demonstrated that stromal cell targeted CAR T cells, in particular CAR T cells that target fibroblast activation protein (FAP), can effectively infiltrate, and inhibit tumor growth in mouse models of pancreatic ductal adenocarcinomas (PDAC) due to their capacity to deplete stromal cells and extracellular matrix (ECM) that otherwise present a barrier to adoptive cell therapies. However, the kinetics of tumor infiltration by FAP-CAR T cells, and the cell-cell and cell-matrix interactions that contribute to their anti-tumor activity are poorly understood. A better understanding FAP-CAR T-cell kinetics and intratumoral interactions should provide insights into the requirements for successful adoptive cell therapies in solid tumors. By combining immunostaining and real-time two-photon microscopy in tumor fragments of PDAC, we found that stromal cell targeted FAP-CAR T cells can efficiently traffic into tumors. Initially (days 1-3) FAP-CAR T cells were enriched in the stroma surrounding tumor nests but excluded from the tumor nests per se. While associated with the stroma rich region, the CAR T cells appeared activated and T cell motility was observed in loose collagen regions, but T cells migrated poorly in dense matrix areas. Aligned collagen fibers in the tumor boarder dictated the migratory trajectory of T cells and restricted them from entering tumor nests. By day 5 we observed depletion of immunosuppressive stromal cells, dissolution of the fibrillar collagen network surrounding tumor nests and infiltration of FAP-CAR T cells into tumor nests. Treatment with hyaluronidase increased the ability of T cells to infiltrate the tumor nest. Thus, FAP-CAR T cell-mediated ablation of immunosuppressive FAP+ stromal cells and disruption of the desmoplastic stroma they generate, can enhance accumulation and functionality of CAR-T cell therapy in the context of highly desmoplastic solid tumors. Citation Format: Zebin Xiao, Leslie A. Hopper, Meghan C. Kopp, Emily McMillan, Yue Li, Richard L. Barrett, Ellen Puré. Visualization of cell to cell and cell to matrix interactions in the disruption of tumor-promoting desmoplasia by adoptive transfer of fibroblast activation protein targeted chimeric antigen receptor (CAR) T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2475.
