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2024

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Harvard Medical School/Peking University collaboration reveals genome-wide gene editing during early oncogenesis!

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Cancer cells edit gene expression to evade immune surveillance. However, genome-wide studies of gene editing during early oncogenesis are lacking.

August 21, 2024, Harvard Medical SchoolJudy Lieberman, Winston Hide and Peking University Zhang Ying jointly communicate inNature Immunology（IF=27.7）Published online entitled"Tumor editing suppresses innate and adaptive antitumor immunity and is reversed by inhibiting DNA methylation"'s research paper,The study showedTumor editing suppresses innate and adaptive antitumor immunity and reverses it by suppressing DNA methylation.

Here, the researchers used single-cell RNA sequencing to unbiased identify edited genes in a genetically engineered mouse model of breast cancer (GEMM). Advanced tumors suppress anti-tumor immune genes and reduce communication between infiltrating immune cells and tumor immune cells. In the list of down-regulated tumor genes, mainly innate immune genes, especially interferon-stimulated genes, while genes regulating intracellular malignancies are mostly not edited. Initial and activated CD8 in early tumors+ T cells are replaced in advanced tumors by depleted or precursor-depleted cells.Low-dose decitabine can reverse the suppression of immune genes by inhibiting DNA methylation, thereby inhibiting tumor growth and restoring immune control, increasingtumor infiltrating lymphocytesreduce the number, function and memory of myeloid suppressor cells.Decitabine induces important interferons, pyroptosis and necrosis genes, inflammatory cell death, and immune control in GEMM, implanted breast, and melanoma.

The clinical success of immunotherapy clearly shows that immune cells can control tumor growth. However, most solid cancers do not respond to current immunotherapies. While immune surveillance limits and eliminates some newly formed immunogenic tumors, tumors that grow to cause disease rapidly evolve to resist immune surveillance and evade immune control. Tumors edit their gene expression to avoid immune recognition and clearance.Editing can be achieved by gene mutation, amplification, deletion, and/or epigenetic modification of gene expression.Immune evasion tumor clones can also inhibit cytotoxic lymphocyte function by shaping the tumor microenvironment (tumor microenvironment, TME), further promoting immune evasion.

Previous immunoediting studies have primarily examined genes and/or pathways that activate anti-tumor T cells. Down-regulation of antigen processing and presentation, checkpoint receptor ligands, up-regulation of immunosuppressive cytokines and "don't eat me" signals,TMEPoor recruitment and rejection of immune cells and immunosuppressive TMEs are known tumor immune evasion strategies.Tumor antigens are mutated and epigenetic silenced during tumor development in immunologically normal but not immunodeficient mice, suggesting that immune selection utilizes genetic and epigenetic mechanisms to reduce tumor immunoreactivity.

Stimulation of T-cell effector function and memory relies on danger signals that activate innate immunity, recruit immune cells to danger sites, and allow immune cells to distinguish between self and non-self,Or in the case of tumors, normal cells are derived from transformed cells. Without danger signals, lymphocytes quickly become resistant to the tumor. DNA promoter hypermethylation inhibits congenitalimmune interferon(IFN), necrosis, and pyroptosis signaling pathways, which have been described in some cancers.Because new tumors are difficult to detect, genome-wide studies of gene expression changes during early tumorigenesis have not been performed. The extent to which tumor gene editing involves genes that suppress immunity versus genes that promote intrinsic cell malignancy is unclear.
Here, the authors utilize the induced MMTV driveErbb2D16Oncogene-generated aggressive breast cancer GEMM to unbiased identify gene expression repressed during early tumorigenesis. Single-cell RNA sequencing (scRNA-seq) compared early GEMM tumors 1 week after oncogene induction with tumors formed 1 month later and found that most of the suppressed genes are involved in immune signaling, particularly innate immunity, including IFN andIFNStimulatory genes (ISGs).The study suggests that immunoediting relies primarily on epigenetic regulation, as genes that are suppressed during immunoediting overlap with those that are suppressed by low-dose DAC.DNMTsImmune control can be restored. Consistent,DACIncreased chromatin accessibility of DNA demethylation and immune genes.This study reveals how TILs alter their phenotype, gene expression, function, and interaction with tumor cells early in tumorigenesis. T-cell exhaustion occurs rapidly, occurring within 1 month after oncogene induction.

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