Placental Site Trophoblastic Tumor Acquires Immune Functions by Incorporating Host Maternal Genes

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Abstract
Although it was proposed that cell fusion of cancer cells with leukocytes creates mobile hybrids with a metastatic phenotype, it has been difficult to genetically confirm cell fusion events in human cancer in vivo. Here, we experienced 4 cases of placental site trophoblastic tumor (PSTT) that produced immunoglobulin (Ig). Three cases showed recurrence and responded well to pembrolizumab therapy. Among them, we could analyze temporal changes in the genetic profiles on one case of daughter‐derived PSTT, which relapsed after pembrolizumab therapy. In this case, we found that PSTT incorporated the exogenous genes from host maternal cells. The rearrangement patterns of Ig genes and protein expressions sequentially increased. By analyzing single‐nucleotide variants, PSTT incorporated daughter‐non‐inherited maternal alleles (DNIMA), including the Ig lambda and HLA‐DQA2 loci. Protein expressions of TLR10 and SIGLEC10 increased during tumor progression concomitantly with DNIMA incorporation. DNIMA mapping indicates the incorporation of exogenous maternal genes was widely distributed through the whole chromosomes, suggesting the involvement of cell fusion in gene transfer mechanisms. These findings indicate that PSTT sequentially incorporated exogenous genes from maternal cells to express immune‐related molecules and suggest that cancer cells acquired B cell‐related functions, including Ig production by cell fusion with host immune cells.
Funding Information
  • Japan Agency for Medical Research and Development (19cm0106610h0003)
  • Japan Agency for Medical Research and Development (19gk0110024h0003)
  • Japan Agency for Medical Research and Development (20gk0210016h0003)

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