Suppression of the METTL3-m6A-integrin β1 axis by extracellular acidification impairs T cell infiltration and antitumor activity
Zhe Wang,
Jingzhe Shang,
Yajing Qiu,
Hongcheng Cheng,
Mengyuan Tao,
Ermei Xie,
Xin Pei,
Wenhui Li,
Lianjun Zhang,
Aiping Wu,
Guideng Li
Affiliations
Zhe Wang
National Key Laboratory of Immunity and Inflammation, and CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, China
Jingzhe Shang
National Key Laboratory of Immunity and Inflammation, and CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, China
Yajing Qiu
National Key Laboratory of Immunity and Inflammation, and CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, China
Hongcheng Cheng
National Key Laboratory of Immunity and Inflammation, and CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, China
Mengyuan Tao
National Key Laboratory of Immunity and Inflammation, and CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, China
Ermei Xie
National Key Laboratory of Immunity and Inflammation, and CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, China
Xin Pei
National Key Laboratory of Immunity and Inflammation, and CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, China
Wenhui Li
National Key Laboratory of Immunity and Inflammation, and CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, China
Lianjun Zhang
National Key Laboratory of Immunity and Inflammation, and CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, China; Corresponding author
Aiping Wu
National Key Laboratory of Immunity and Inflammation, and CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, China; Corresponding author
Guideng Li
National Key Laboratory of Immunity and Inflammation, and CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, China; Corresponding author
Summary: The acidic metabolic byproducts within the tumor microenvironment (TME) hinder T cell effector functions. However, their effects on T cell infiltration remain largely unexplored. Leveraging the comprehensive The Cancer Genome Atlas dataset, we pinpoint 16 genes that correlate with extracellular acidification and establish a metric known as the “tumor acidity (TuAci) score” for individual patients. We consistently observe a negative association between the TuAci score and T lymphocyte score (T score) across various human cancer types. Mechanistically, extracellular acidification significantly impedes T cell motility by suppressing podosome formation. This phenomenon can be attributed to the reduced expression of methyltransferase-like 3 (METTL3) and the modification of RNA N6-methyladenosine (m6A), resulting in a subsequent decrease in the expression of integrin β1 (ITGB1). Importantly, enforced ITGB1 expression leads to enhanced T cell infiltration and improved antitumor activity. Our study suggests that modulating METTL3 activity or boosting ITGB1 expression could augment T cell infiltration within the acidic TME, thereby improving the efficacy of cell therapy.
