Targeting CD147 For T To NK Lineage Reprogramming And Tumor Therapy

As a multifunctional transmembrane glycoprotein, CD147 is highly expressed on the surface of numerous tumor cells and tumor stem cells to promote invasion and metastasis. Targeting these cells with CD147-specific antibodies has been validated and commercialized as an effective approach for lung and liver cancer therapy. In the immune system, CD147 is recognized as a co-stimulatory receptor and impacts the outcome of thymic selection. Using T cell-specific deletion, we showed here that in thymus CD147 is indispensable for the stable αβT cell lineage commitment: loss of CD147 biases both multipotent DN and fully committed DP cells into innate NK-like lineages. Mechanistically, CD147 deficiency results in impaired Wnt signaling and expression of BCL11 b, a master transcription factor in determining T cell identity. In addition, functional blocking of CD147 by antibody phenocopies genetic deletion to enrich NK-like cells in the periphery. Furthermore, using a melanoma model and orthotopic liver cancer transplants, we showed that the augmentation of NK-like cells strongly associates with resistance against tumor growth upon CD147 suppression. Therefore, besides its original function in tumorigenesis, CD147 is also an effective surface target for immune modulation in tumor therapy.Part Ⅰ:Phenotypic changes of CD147^T-KO mice.Our department successfully obtained a conditional gene targeting mouse, CD147^T-KO mice, and simply analyzed its phenotypes. In order to understand the role of CD147 during T cell development more clearly, we have re-analyzed and re-studied the CD147^T-KO mice. In this part, we found that the size and weight of thymus in CD147^T-KO mice were smaller compared with the control wild-type mice, and cell types also changed; the size and weight of the peripheral lymphoid organs, as well as types of lymphocytes had no significant difference; then, we have analyzed the changes of NK/NKT-like cells and found NK/NKT-like cells increased. Combining all results, we have identified that CD147 knockout in T lymphocytes influence T cell development, and these results further validate CD147 is essential for the thymus development, and also provide a good start for us to study the relationship between CD147 and T cell development.Part Ⅱ:CD147 influences the development of NKT / NK-like cells.CD147 knockout in T cells block DN3 to DN4 stage during T-cell development, and promote the innate-like cells production. Where excessive generation of NK/NKT-like cells derived from? what mechanism is associated with CD147 on T cell development? In this part, we used a standard T cells development of culture system in vitro, which is a co-culture system of OP9-DL1 stromal cells and hematopoietic stem cell or T cell. The source of NK/NKT-like cells in vitro were analyzed, and we found that the increased NK/NKT-like cells were come from different developmental stages of T cell lineage reprogramming, and loss of CD147 impact the expression of TCF1 in Wnt signaling pathway and then affect the Bcl11 b expression and T cell development.Part Ⅲ:CD147 and tumor immune therapy in mice.CD147, as a wide range and reliable biomarkers of tumor, significantly higher express on tumor cell surface in a variety of tissues, and is associated with cancer treatment. In our study, CD147 contributed in the thymus development and is closely related to NK/NKT cells production, and we also have in-depth study about its molecular mechanisms. We suspect that the relationship between CD147 and NK/NKT cells will become another mechanism about anti-tumor effect of CD147 antibody. Tumor model must be carried out to study on this issue. Mouse melanoma model was used to study NK/NKT cells, and mouse orthotopic liver tumor was a main tool to study anti-tumor effect of CD147 antibody. Therefore, we used the two mouse models to study the relationship between CD147 and NK/NKT cells, and found that CD147 antibody therapy can decreased tumor growth, and this anti-tumor effect associated with NK-like cells. This part further expands mechanisms of CD147 antibody anti-tumor effect.