Visualization of human T lymphocyte-mediated eradication of cancer cells in vivo
Menée à l'aide d'un modèle de poisson-zèbre, cette étude met en évidence l'intérêt d'un système de visualisation, basé sur le marquage des cellules cancéreuses par un colorant de viabilité (calcéine), pour déterminer l'effet des lymphocytes infiltrant la tumeur et des lymphocytes CAR-T sur les cellules cancéreuses
The clinical efficacy of immunotherapy in cancer patients is limited. We have developed a zebrafish model that allows us to visualize the metastatic cancer cell-killing effect by tumor-infiltrating lymphocytes and chimeric antigen receptor T cells in vivo at the single-cell level. This in vivo model accurately predicts clinical efficacy of T cell-mediated cancer therapy. Our data provide an in vivo platform for validating antimetastatic effects by human T cell-mediated immunotherapy. Based on our findings, it is highly recommended that anticancer effects of T cells isolated from cancer patients or genetically propagated T cells should be evaluated in this in vivo animal model before clinical application. If so, millions of cancer patients might benefit from our work.Lymphocyte-based immunotherapy has emerged as a breakthrough in cancer therapy for both hematologic and solid malignancies. In a subpopulation of cancer patients, this powerful therapeutic modality converts malignancy to clinically manageable disease. However, the T cell- and chimeric antigen receptor T (CAR-T) cell-mediated antimetastatic activity, especially their impacts on microscopic metastatic lesions, has not yet been investigated. Here we report a living zebrafish model that allows us to visualize the metastatic cancer cell killing effect by tumor- infiltrating lymphocytes (TILs) and CAR-T cells in vivo at the single-cell level. In a freshly isolated primary human melanoma, specific TILs effectively eliminated metastatic cancer cells in the living body. This potent metastasis-eradicating effect was validated using a human lymphoma model with CAR-T cells. Furthermore, cancer-associated fibroblasts protected metastatic cancer cells from T cell-mediated killing. Our data provide an in vivo platform to validate antimetastatic effects by human T cell-mediated immunotherapy. This unique technology may serve as a precision medicine platform for assessing anticancer effects of cellular immunotherapy in vivo before administration to human cancer patients.All study data are included in the main text and SI Appendix.
Proceedings of the National Academy of Sciences , résumé, 2019