LAUSR

Weak immunogenicity of tumor cells is a root cause for the ultimate failure of immunosurveillance and immunotherapy. Although tumor evolution can be shaped by immunoediting toward a less immunogenic phenotype, mechanisms governing the initial immunogenicity of primordial tumor cells or original cancer stem cells remain obscure. Here, using a single tumor-repopulating cell (TRC) to form tumors in immunodeficient or immunocompetent mice, we demonstrated that immunogenic heterogeneity is an inherent trait of tumorigenic cells defined by the activation status of signal transducer and activator of transcription 1 (STAT1) protein in the absence of immune pressure. Subsequent investigation identified that the RNA binding protein cold shock domain–containing protein E1 (CSDE1) can promote STAT1 dephosphorylation by stabilizing T cell protein tyrosine phosphatase (TCPTP). A methyltransferase SET and MYN domain–containing 3 (SMYD3) was further identified to mediate H3K4 trimethylation of CSDE1 locus, which was under the regulation of mechanotransduction by cell-matrix and cell-cell contacts. Thus, owing to the differential epigenetic modification and subsequent differential expression of CSDE1, nascent tumorigenic cells may exhibit either a high or low immunogenicity. This identified SMYD3-CSDE1 pathway represents a potential prognostic marker for cancer immunotherapy effectiveness that requires further investigation. Description The SMYD3-CSDE1 axis regulates the immunogenicity of nascent tumor cells and presents as a target for tumor immunotherapy. Shocking the immune system One way tumors overcome immunosurveillance and immunotherapy is through their inherent lack of immunogenicity, however, the mechanisms underlying this are not well understood. Here, Lv et al. have utilized a single tumor-repopulating cell model in mice to demonstrate that immunogenic heterogeneity is regulated by signal transducer and activator of transcription 1 (STAT1) and cold shock domain containing protein E1 (CSDE1). CSDE1 is additionally regulated epigenetically by mechanotransduction and has the propensity to exhibit either high or low immunogenicity. Thus, CSDE1 expression could be a potential marker for cancer immunotherapy response that requires further investigation. — DH