Cancer cell subpopulation and host crosstalk during metastasis of pancreatic ductal adenocarcinoma (PDAC)
Final Report Abstract
In this project, we have investigated pancreatic cancer cell-T cell interactions and focused on distinct cancer cell-intrinsic mechanisms in modulating their response to T cell attack. For that, we have established a 3D cancer spheroid/tumor-educated (ed)T cell co-culture system and successfully isolated edT cell-resistant cancer cell subpopulations. We revealed their differential gene expression and signaling pathways compared to sensitive cells with a combination of transcriptomic analyses, as well as cytometric and immunohistochemistry techniques. A decreased CXCL12/CXCR4 signaling showed to contribute to edT cell-resistance in PDAC cells. Adding back CXCL12 to resistant cells in edT cell-culture improved effector T cell functionality and re-sensitized them to T cell attack. This new methodological approach facilitates to dissect mechanisms of pancreatic cancer cell sensitivity and resistance to T cell-mediated cytotoxicity in an unprecedented way and has the potential to identify new druggable targets in cancer cell – T cell crosstalk that could be applied for T cell-based immunotherapies or combinatorial treatment regimen together with targeted anticancer agents in patients with pancreatic ductal adenocarcinoma (PDAC). The biggest surprise of this project was the observation that T cell-mediated killing rates are highly distinct between different pancreatic cancer cell population derived from the same tumor. This suggests that differential cancer cell-autonomous mechanisms contribute to regulate resistance and sensitivity to T cell attack. The paradigm that pancreatic cancer is generally “cold”, meaning impenetrable for T cells and thus primarily resistant to immunotherapy does not hold true. Targeting distinct resistance mechanisms of cancer cell subpopulations might improve T cell response and synergize with standard of care treatment options.
Publications
- Monitoring Cancer Cell Invasion and T-Cell Cytotoxicity in 3D Culture. J Vis Exp. 2020; (160)
Lin YN, Nasir A, Camacho S, Berry DL, Schmidt MO, Pearson GW et al.
(See online at https://doi.org/10.3791/61392) - (2022). Biological, biomechanical and translational aspects of cell movement in health and disease. Book chapter 6: Cell migration. Michael Schnoor, Sean Sun, Lei-Miao Yin. Elsevier Academic Press
Lin YN, Wellstein A
(See online at https://doi.org/10.1016/B978-0-323-90195-6.00011-5) - Impaired CXCL12 signaling contributes to resistance of pancreatic cancer subpopulations to T cell-mediated cytotoxicity. OncoImmunology 2022; 11: 2027136
Lin YN, Schmidt MO, Sharif GM, Vietsch EE, Kiliti AJ, Barefoot ME, Riegel AT and Wellstein A
(See online at https://doi.org/10.1080/2162402x.2022.2027136)
