Loss of YTHDF1 in gastric tumors restores sensitivity to antitumor immunity by recruiting mature dendritic cells

Abstract

BackgroundGastric cancer (GC) is one of the most common cancer worldwide. We analyzed the expression of m6A regulatory genes in GC cohorts and revealed that YTHDF1 was uniquely upregulated in GC as compared with adjacent normal tissues. In this study, we analyzed the role of YTHDF1 in GC cells and modulation of the tumor immune microenvironment.MethodsThree GC cohorts (cohort 1, n=101; cohort 2, n=278, and the Cancer Genome Atlas cohort, n=375) were analyzed for YTHDF1 expression. Function of YTHDF1 in GC was determined in GC cell lines. Role of YTHDF1 in antitumor immunity was investigated in allograft models.ResultsYTHDF1 is upregulated in GC compared with adjacent normal tissues, and high YTHDF1 expression was correlated with poor survival of patients with GC at mRNA (p=0.016) and protein levels (p=0.039). Loss of YTHDF1 in human (AGS, BGC823, MKN74) or mouse (YTN16) GC cell lines inhibited cell growth and colony formation in vitro. Strikingly, syngeneic YTN16 tumors with loss of YTHDF1 underwent complete remission in immunocompetent mice, while a lesser effect was found in immunodeficient mice. Consistently, YTHDF1 loss in GC tumors led to recruitment of mature dendritic cells (DCs) with increased MHCII expression and interleukin-12 (IL-12) secretion, which in turn, promoted CD4+ and CD8+ T cells infiltration with increased interferon-γ (IFN-γ) secretion. Loss of YTHDF1 mediated the overexpression of IFN-γ receptor 1 and JAK/STAT1 signaling pathway in tumor cells, which might contribute to restored sensitivity to antitumor immunity. In addition, pre-emptive exposure of YTN16 tumors with YTHDF1 loss triggered a potent antitumor immune response on rechallenge with wild-type YTN16 cells, implying that YTHDF1 loss induced a lasting systemic antitumor immunity.ConclusionsYTHDF1 is overexpressed in GC and promotes GC by inducing cell proliferation and repression of DCs-mediated antitumor immune response. YTHDF1 is a promising therapeutic target for GC treatment.

N6-Methyladenosine RNA-Binding Protein YTHDF1 in Gastrointestinal Cancers: Function, Molecular Mechanism and Clinical Implication

“…As a consequence, ICB therapeutic response is significantly enhanced in YTHDF1knockout mice as compared to wildtype mice. Consistently, our recent study implied the role of YTHDF1 in repressing DCs function in GC [17]. Loss of YTHDF1 in tumor cells leads to the recruitment of mature DCs in the tumor, which in turn promotes the infiltration of T helper cells and cytotoxic T cells, as well as the increased production of cytotoxic cytokines.…”

“…In terms of clinical application, YTHDF1 is reported to be an independent marker for the diagnosis and prognosis of GI cancer [ 17 , 29 ]. Interestingly, several studies have suggested that YTHDF1 and its downstream signaling pathways might serve as novel therapeutic targets against GI cancers, given the accumulating evidence showing its role in mediating drug resistance.…”

“…Although many regulatory mechanisms have been discovered, there are still many unclear and controversial mechanisms due to the complexity of YTHDF1 regulation. Given the dynamic nature of m 6 A modifications, it is likely that the overall effect of YTHDF1 can vary in a context-and cell type-specific manner [17,83]. The exact role of YTHDF1 in GI cancers would be better elucidated using conditional, transgenic mice models that manipulate YTHDF1 in specific cell types, such as tumor cells or immune cells, in order to reveal the exact role of YTHDF1 in GI cancer development.…”

“…Recent evidence indicates that YTHDF1 expression in cancer cells could modify the GC immune microenvironment. Bai et al, demonstrated that the loss of YTHDF1 in GC tumors provokes the complete disease remission in immunocompetent mice, but not in immunodeficient mice [ 17 ]. In immunocompetent mice, the loss of YTHDF1 stimulates the recruitment of mature dendritic cells (DCs) to GC with higher expression of major histocompatibility complex II and interleukin-12 secretion, thereby promoting CD4 + and CD8 + T cells infiltration.…”

Crosstalk among m6A RNA methylation, hypoxia and metabolic reprogramming in TME: from immunosuppressive microenvironment to clinical application

“…For example, YTHDF1 induces lysosomal protease expression by recognizing its m 6 A methylation-tagged mRNA and enhancing translation efficiency, further resulting in the inability of DCs to consistently induce tumor neoantigen production and impeding antigen-specific activation of CD8 + T cells [ 123 ]. Conversely, YTHDF1 deficiency in gastric cancer promotes the recruitment of mature DCs, which further stimulate MHCII expression and IL-12 secretion, in turn, increasing CD4 + and CD8 + T cell infiltration and IFN-γ secretion that potentially contribute to restoration of tumor immune sensitivity [ 124 ]. Therefore, YTHDF1 deletion may enhance antitumor immunity by facilitating interactions with DCs, rather than promoting their differentiation and proliferation, supporting a potential role of YTHDF2 as a tumor immunosuppressive factor.…”