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

• Published in: Journal for immunotherapy of cancer Vol. 10; no. 2; p. e003663
• Main Authors: Bai, Xiaowu, Wong, Chi Chun, Pan, Yasi, Chen, Huarong, Liu, Weixin, Zhai, Jianning, Kang, Wei, Shi, Yu, Yamamoto, Masami, Tsukamoto, Tetsuya, Nomura, Sachiyo, Chiu, Philip, Yu, Jun, Kwok-wai Ng, Enders
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd 01.02.2022; BMJ Publishing Group LTD; BMJ Publishing Group
• Series: Original research
• Subjects: Animals; Basic Tumor Immunology; Cancer; Cell Line, Tumor; Cohort Studies; CRISPR; Cytokines; Dendritic cells; Dendritic Cells - immunology; Ethics; Female; Flow cytometry; Gastric cancer; Gene expression; Humans; Immunotherapy; Immunotherapy - methods; Male; Mice; Mortality; Plasmids; Proteins; Reagents; RNA-Binding Proteins - metabolism; Stomach Neoplasms - immunology; Stomach Neoplasms - mortality; Survival Analysis; Tumors; United States > US; China; Germany; dendritic cells; immunotherapy
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2021-003663

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.