Article ; Online: Cell fusion upregulates PD-L1 expression for evasion from immunosurveillance.
2023 Volume 31, Issue 1, Page(s) 158–173
Abstract: MSCs (mesenchymal stem cells), responsible for tissue repair, rarely undergo cell fusion with somatic cells. Here, we show that ~5% of bladder cancer cells (UMUC-3) fuses with bone marrow-derived MSC (BM-MSC) in co-culture and maintains high ... ...
| Abstract | MSCs (mesenchymal stem cells), responsible for tissue repair, rarely undergo cell fusion with somatic cells. Here, we show that ~5% of bladder cancer cells (UMUC-3) fuses with bone marrow-derived MSC (BM-MSC) in co-culture and maintains high tumorigenicity. In eleven fusion cell clones that have been established, Mb-scale deletions carried by the bladder cancer cells are mostly absent in the fusion cells, but copy number gains contributed by the cancer cells have stayed. Fusion cells exhibit increased populations of mitotic cells with 3-polar spindles, indicative of genomic instability. They grow faster in vitro and exhibit higher colony formation in anchorage-independent growth assay in soft agar than the parent UMUC-3 does. Fusion cells develop tumors, after 4 weeks of time lag, as efficiently as the parent UMUC-3 does in xenograft experiments. 264 genes are identified whose expression is specifically altered in the fusion cells. Many of them are interferon-stimulated genes (ISG), but are activated in a manner independent of interferon. Among them, we show that PD-L1 is induced in fusion cells, and its knockout decreases tumorigenesis in a xenograft model. PD-L1 is induced in a manner independent of STAT1 known to regulate PD-L1 expression, but is regulated by histone modification, and is likely to inhibit phagocytosis by PD1-expressing macrophages, thus protecting cancer cells from immunological attacks. The fusion cells overexpress multiple cytokines including CCL2 that cause tumor progression by converting infiltrating macrophages to tumor-associated-macrophage (TAM). The results present mechanisms of how cell fusion promotes tumorigenesis, revealing a novel link between cell fusion and PD-L1, and underscore the efficacy of cancer immunotherapy. |
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| MeSH term(s) | Humans ; B7-H1 Antigen ; Cell Fusion ; Monitoring, Immunologic ; Interferons ; Urinary Bladder Neoplasms ; Carcinogenesis ; Cell Line, Tumor |
| Chemical Substances | B7-H1 Antigen ; Interferons (9008-11-1) |
| Language | English |
| Publishing date | 2023-11-21 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 1212513-1 |
| ISSN | 1476-5500 ; 0929-1903 |
| ISSN (online) | 1476-5500 |
| ISSN | 0929-1903 |
| DOI | 10.1038/s41417-023-00693-0 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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