TY - JOUR
T1 - Loss of YTHDF1 in gastric tumors restores sensitivity to antitumor immunity by recruiting mature dendritic cells
AU - Bai, Xiaowu
AU - Wong, Chi Chun
AU - Pan, Yasi
AU - Chen, Huarong
AU - Liu, Weixin
AU - Zhai, Jianning
AU - Kang, Wei
AU - Shi, Yu
AU - Yamamoto, Masami
AU - Tsukamoto, Tetsuya
AU - Nomura, Sachiyo
AU - Chiu, Philip
AU - Yu, Jun
AU - Ng, Enders Kwok Wai
N1 - Publisher Copyright:
© 2022 BMJ Publishing Group. All rights reserved.
PY - 2022/2/22
Y1 - 2022/2/22
N2 - Background Gastric cancer (GC) is one of the most common cancer worldwide. We analyzed the expression of m 6 A 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. Methods Three 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. Results YTHDF1 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- 3) secretion. Loss of YTHDF1 mediated the overexpression of IFN-γreceptor 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. Conclusions YTHDF1 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.
AB - Background Gastric cancer (GC) is one of the most common cancer worldwide. We analyzed the expression of m 6 A 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. Methods Three 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. Results YTHDF1 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- 3) secretion. Loss of YTHDF1 mediated the overexpression of IFN-γreceptor 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. Conclusions YTHDF1 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.
KW - dendritic cells
KW - immunotherapy
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U2 - 10.1136/jitc-2021-003663
DO - 10.1136/jitc-2021-003663
M3 - Article
C2 - 35193930
AN - SCOPUS:85125156894
SN - 2051-1426
VL - 10
JO - Journal for ImmunoTherapy of Cancer
JF - Journal for ImmunoTherapy of Cancer
IS - 2
M1 - e003663
ER -
