Targeting CD147 for T to NK Lineage Reprogramming and Tumor Therapy

Abstract

CD147 is highly expressed on the surface of numerous tumor cells to promote invasion and metastasis. Targeting these cells with CD147-specific antibodies has been validated 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 αβ T cell lineage commitment: loss of CD147 biases both multipotent DN (double negative) and fully committed DP (double positive) cells into innate NK-like lineages. Mechanistically, CD147 deficiency results in impaired Wnt signaling and expression of BCL11b, 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.

CD147 deficiency in T cells prevents thymic involution by inhibiting the EMT process in TECs in the presence of TGFβ

“…Previously, we reported that CD147 depletion in T cells resulted in deficient thymic development and that both the size and the weight of the thymus were less in the CD147 T-KO mice than they were in the wild-type mice 6 weeks after birth. 33 Interestingly, with the extension of our observation time, we found that the weight of and T-cell number in the thymus in the CD147 T-KO mice and wild-type mice were found to be similar 12 weeks after birth (Fig. 1a–c ).…”

“… 30 – 32 In our previous studies, we found that, in young mice, CD147 depletion in thymocytes (CD147 T-KO ) resulted in decreased thymus size, thymic cellularity loss, and diminished T-cell lineage cell numbers, which were accompanied by increases in the number of various lymphocyte populations with innate immunological functions, such as γδ T cells, NKT-like cells, and NK-like cells. 33 In another interesting finding, the size and weight of the thymus in CD147 T-KO mice decreased more slowly than did those in wild-type mice during aging. This result indicates that CD147 on T cells may be involved in thymic involution.…”

CD98-induced CD147 signaling stabilizes the Foxp3 protein to maintain tissue homeostasis

“…Previously, we reported that the early deletion of CD147 expression in thymocytes (CD147 T-KO mice [ 24 ]) leads to the enrichment of lymphocytes with innate features [ 22 ]. Moreover, in these CD147 T-KO mice, while Treg development in the thymus appeared to be normal, the ratio of Foxp3+ Tregs was reduced in peripheral organs, including lymph nodes, spleen, and circulating blood (Fig.…”

“…Studies of CD147 T-KO mice on the C57Bl/6 background have been previously published [ 22 ]. Wild-type (WT) female C57BL/6 mice were purchased from the Fourth Military Medical University, Laboratory Animal Center, and white C57BL/6 mice were obtained from the Biomedical Analysis Center of the Third Military Medical University.…”

How could we forget immunometabolism in SARS-CoV2 infection or COVID-19?

“…Hence, NK cells become confused to act as stimulatory immune cells or exert immunosuppressive action in the event of a cytokine storm seen in severe COVID-19 patients. However, NK cells express CD147, another receptor for SARS-CoV2 entry, and also possess a functional renin-angiotensin system (RAS) [196,197]. Thus SARS-CoV2 virus can infect NK cells, but antiviral IFN-based and cytokine-based immune responses do not take place to counter the pathogen due to the viral strategies of hijacking.…”