An Oncogenic Alteration Creates a Microenvironment that Promotes Tumor Progression by Conferring a Metabolic Advantage to Regulatory T Cells

Shogo Kumagai, Yosuke Togashi, Chika Sakai, Akihito Kawazoe, Masahito Kawazu, Toshihide Ueno, Eiichi Sato, Takeshi Kuwata, Takahiro Kinoshita, Masami Yamamoto, Sachiyo Nomura, Tetsuya Tsukamoto, Hiroyuki Mano, Kohei Shitara, Hiroyoshi Nishikawa

研究成果: Article

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Only a small percentage of patients afflicted with gastric cancer (GC) respond to immune checkpoint blockade (ICB). To study the mechanisms underlying this resistance, we examined the immune landscape of GC. A subset of these tumors was characterized by high frequencies of regulatory T (Treg) cells and low numbers of effector T cells. Genomic analyses revealed that these tumors bore mutations in RHOA that are known to drive tumor progression. RHOA mutations in cancer cells activated the PI3K-AKT-mTOR signaling pathway, increasing production of free fatty acids that are more effectively consumed by Treg cells than effector T cells. RHOA mutant tumors were resistant to PD-1 blockade but responded to combination of PD-1 blockade with inhibitors of the PI3K pathway or therapies targeting Treg cells. We propose that the metabolic advantage conferred by RHOA mutations enables Treg cell accumulation within GC tumors, generating an immunosuppressive TME that underlies resistance to ICB.

元の言語English
ページ(範囲)187-203.e8
ジャーナルImmunity
53
発行部数1
DOI
出版物ステータスPublished - 14-07-2020

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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    Kumagai, S., Togashi, Y., Sakai, C., Kawazoe, A., Kawazu, M., Ueno, T., Sato, E., Kuwata, T., Kinoshita, T., Yamamoto, M., Nomura, S., Tsukamoto, T., Mano, H., Shitara, K., & Nishikawa, H. (2020). An Oncogenic Alteration Creates a Microenvironment that Promotes Tumor Progression by Conferring a Metabolic Advantage to Regulatory T Cells. Immunity, 53(1), 187-203.e8. https://doi.org/10.1016/j.immuni.2020.06.016