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

Immunity. 2020 Jul 14;53(1):187-203.e8. doi: 10.1016/j.immuni.2020.06.016. Epub 2020 Jul 7.


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.

Keywords: PI3K inhibitor; RHOA mutation; fatty acid metabolism; gastric cancer; non-inflamed tumor; regulatory T cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4 Lymphocyte Count
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Line, Tumor
  • Chemokine CXCL10 / biosynthesis
  • Chemokine CXCL11 / biosynthesis
  • Fatty Acids, Nonesterified / biosynthesis
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Nude
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors / pharmacology
  • Programmed Cell Death 1 Receptor / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / immunology
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / immunology
  • Stomach Neoplasms / pathology
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism*
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Microenvironment / immunology
  • rhoA GTP-Binding Protein / genetics*


  • CXCL10 protein, human
  • CXCL11 protein, human
  • Chemokine CXCL10
  • Chemokine CXCL11
  • Fatty Acids, Nonesterified
  • Immune Checkpoint Inhibitors
  • PDCD1 protein, human
  • Phosphoinositide-3 Kinase Inhibitors
  • Programmed Cell Death 1 Receptor
  • RHOA protein, human
  • MTOR protein, human
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • rhoA GTP-Binding Protein