Epigenetic modification of CSDE1 locus dictates immune recognition of nascent tumorigenic cells

Abstract

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.

Epigenetic escape of immunosurveillance by malignant cell precursors

“…Thus, inoculating a pure population of CSDE1 High B16 cells into immunocompetent C57BL/6 mice resulted in the recovery (30 days later) of a population including 10–15% of CSDE1 Low cells. Similar results were obtained upon inoculating a pure population of CSDE1 Low B16 cells (Lv et al , 2023). These observations suggested that CSDE1 levels are regulated by an epigenetic mechanism sensitive to the TRC microenvironment.…”

“…In line with this notion, CSDE1 was found to bind to the Ptpn2 mRNA via a specific nucleotide domain (AACG) in the Ptpn2 3′ UTR and stabilize it. Moreover, Ptpn2 deletion increased STAT1 phosphorylation and surface‐exposed MHC Class I molecules in B16 cells, two effects that could be reverted by TCPTP overexpression (Lv et al , 2023). This formally identified TCPTP as the CSDE1‐regulated inhibitor of TRC immunogenicity.…”

“…Moreover, Smyd3 deletion resulted in global H3K4me3 demethylation, including at the Csde1 promoter, coupled with CSDE1 and TCPTP downregulation, increased STAT1 phosphorylation, and elevated levels of membrane‐exposed MHC Class I molecules. Finally, SMYD3 expression appeared to be largely restricted to the periphery of TRC‐driven tumor spheroids (Lv et al , 2023), suggesting a role for intratumoral heterogeneity and the TME in the definition of cell‐intrinsic epigenetic states impacting immunogenicity. While the precise impact of H3K4me3 at the Csde1 promoter on differential Cdse1 transcription remains to be clarified, these findings delineate a novel cancer cell‐intrinsic, SMYD3‐dependent mechanism that enables immunoevasion by TRCs.…”

“…presentation (Pishesha et al, 2022), was not overexpressed in B16 cells lacking Csde1 but exhibited enhanced activating phosphorylation and nuclear localization, both at baseline and upon exposure to IFNG (Lv et al, 2023). These results point to limited STAT1 activation and consequent poor antigen presentation, as to a potential mechanism through which CSDE1 suppresses TRC immunogenicity.…”

“…The EMBO Journal (2023) 42: e114050 See also : Lv et al (2023) A ccording to a widely accepted model, newly transformed cancer cells are efficiently recognized and eliminated by the host immune system until they acquire additional genetic or epigenetic alterations that ultimately drive immunoevasion, culminating with the formation of progressing, clinically relevant neoplasms (Dersh et al, 2021). In this context, the immune system has been largely viewed as a Darwinian selective pressure that shapes the evolution of the tumor microenvironment (TME) towards a poorly immunogenic phenotype (Vitale et al, 2021).…”